Topical compositions for pain relief, manufacture and use

ABSTRACT

The present invention relates to TRPV1 selective agonist compositions including a capsaicinoid, a surfactant and an extended release agent, and to methods of manufacture and methods of providing pain relief as well as treating a variety of disorders with such compositions.

This application is a continuation of U.S. application Ser. No.16/243,317 filed Jan. 9, 2019, which is a continuation of U.S.application Ser. No. 15/939,445 filed Mar. 29, 2018 (now U.S. Pat. No.10,206,892), which is a divisional of U.S. application Ser. No.14/687,566 filed Apr. 15, 2015 (now U.S. Pat. No. 9,956,190), whichclaims priority to U.S. Provisional Application No. 61/979,905 filedApr. 15, 2014, the entire contents of each of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to compositions of transient receptorpotential vanilloid 1 (TRPV1) selective agonists such as capsaicin,methods of manufacture and methods of providing pain relief, as well asmethods of treating a variety of medical conditions.

BACKGROUND OF THE INVENTION

Capsaicin is the main capsaicinoid in capsicum plants including chilipeppers. Capsaicin is a solid at room temperatures with a melting pointof 60-62° C. It is a pungent substance that has long been used for therelief of pain because of its selective action on the small diameterafferent nerve fibers (C fibers and A-delta fibers) that are believed tosignal pain. From studies in animals, capsaicin appears to trigger Cfiber membrane depolarization by opening cation channels permeable tocalcium and sodium.

Capsaicin has been reported to work by depleting a compound calledSubstance P, which is a neuropeptide that functions as aneurotransmitter and promotes pain perception, from the nerve terminalfibers. However, capsaicin also can elicit erythema and/or an intenseburning or stinging sensation upon application. The intense burning orstinging can be intolerable for some. Additionally, it may take morethan a day or two for effectuating actual pain relief, and for theintense burning to stop. Following the initial period of intense burningpain that may be accompanied by erythema, topical capsaicin applicationcauses insensitivity to pain elicited by a variety of noxious stimuli ordisease states. In theory, neurons shut down after they've beenstimulated by capsaicin, so the burning and other unrelatedsensations—including pain—cease. The results from studies testing thelow concentrations of capsaicin present in most over-the-counterproducts (0.075 percent or less) have not been impressive. Many peopleare bothered by the burning sensation, so they don't stick with thetreatment. Current over-the-counter capsaicin products are not effectivefor many people. High-dose capsaicin patches have been developed, butthey require local or regional anesthesia to address the burning andstinging, and therefore are only appropriate for treatment for severechronic pain under the supervision of a physician.

Because of the ability of capsaicin to desensitize nociceptors inperipheral tissues, their potential analgesic effects have been assessedin various clinical trials. However, since the application of capsaicinitself frequently causes burning pain and hyperalgesia apart from theneuropathic pain being treated, patient compliance has been poor and thedropout rates during clinical trials have typically exceeded fiftypercent. The most frequently encountered adverse effect with capsaicinis burning pain at the site of application, particularly in the firstweek of application. This can make it impossible to blind trials and canlead to dropout rates ranging from 33 to 67% (Watson C P et al. “Arandomized vehicle-controlled trial of topical capsaicin in thetreatment of postherpetic neuralgia.” Clinical Therapeutics. 15.3(1993):510-26.) Another factor in compliance is the time delay beforetherapeutic effect is observed. Daily topical applications for at leasta week or two may be required.

Many individuals discontinue the prolonged treatment of topicalcapsaicin prior to the anticipated analgesic effects of capsaicin due tothe intense stinging and burning pain. It was reported that 26 out of 39(66.7%) patients suffering from post-herpetic neuralgia did not toleratethe treatment of a 0.025% capsaicin preparation (Zostrix, Gen Derm,USA). With a 0.075% preparation (Zostrix-HP, Gen Derm, USA), 5 out of 16(31.3%) and 45 out of 74 (60.8%) patients with post-herpetic neuralgiadid not tolerate the long term topical treatment. (Peikert, A. et al.,Topical 0.025% capsaicin in chronic post-herpetic neuralgia: efficacy,predictors of response and long-term course, J. Neurol. 238:452-456,1991; Watanabe, A. et al., Efficacy of capsaicin ointment (Zostrix) inthe treatment of herpetic pain and postherpetic neuralgia, Pain Clinic15:709-713, 1994; Bernstein J. E. et al., Topical capsaicin treatment ofchronic postherpetic neuralgia, J. Am. Acad. Dermatol. 21: 265-270,1989; and Watson C P. N. et al., A randomized vehicle-controlled trialof topical capsaicin in the treatment of postherpetic neuralgia, Clin.Ther. 15:510-526, 1993.)

The spontaneous burning pain and hyperalgesia are believed to be due tointense activation and temporary sensitization of the peripheralnociceptors at the site of capsaicin application. This activation andsensitization occurs prior to the desensitization phase and is a barrierto topical capsaicin use because the burning pain produced compromisespatient's tolerability of treatment.

Capsaicin is believed to relieve pain by causing a localized degradationof the C neuron endings. The activity of capsaicin results from itsbinding to, and activating, an ion channel called vanilloid receptor 1,or VR1. Under normal circumstances, when the VR1 ion channel isactivated, it opens for a short time, causing the C neurons to transmita pain signal toward the brain. When capsaicin binds to, and activatesVR1, it causes a series of events within the cell that degrade thepain-sensing endings, or terminals of the C neuron, thereby preventingthe neuron from transmitting pain signals.

In 1997, a research team led by David Julius of University ofCalifornia, San Francisco showed that capsaicin selectively binds to aprotein known as TRPV1 that resides on the membranes of pain and heatsensing neurons. TRPV1 is a heat activated calcium channel, which opensbetween 37 and 45° C. (98.6 and 113° F., respectively). When capsaicinbinds to TRPV1, it causes the channel to open below 37° C. (normal humanbody temperature), which is why capsaicin is linked to the sensation ofheat. Prolonged activation of these neurons by capsaicin depletespresynaptic substance P, one of the body's neurotransmitters for painand heat. Neurons that do not contain TRPV1 are unaffected. The resultappears to be that the chemical mimics a burning sensation; the nervesare overwhelmed by the influx, and are unable to report pain for anextended period of time. With chronic exposure to capsaicin, neurons aredepleted of neurotransmitters, leading to reduction in sensation of painand blockade of neurogenic inflammation. If capsaicin is removed, theneurons recover.

Although the analgesic effect of capsaicin was thought to be due to adepletion in the pain-causing substance P, recent evidence suggests aprocess of “defunctionalization” of nociceptor fibers is responsible forits analgesic effect. (Anand P, Bley K. Topical capsaicin for painmanagement: therapeutic potential and mechanisms of action of the newhigh-concentration capsaicin 8% patch. Br J. Anaesth. 2011;107(4):490-502.)

Humans have long been exposed to dietary sources of capsaicin-containingspices and to topical preparations used for a variety of medicalindications. This vast experience has not revealed significant orlasting adverse effects of capsaicin exposure. The recent determinationof potential therapeutic effects of capsaicin on unmyelinated sensoryafferent nerve fibers requires diligent consideration of this compoundfor further pharmaceutical development.

Capsaicin is currently marketed for topical administration in the formof over-the-counter, low dose, non-sterile creams and patches, whichtend to be poorly absorbed. There are more than thirty brands of creamsand patches, including CapZasin™ (Chattem) and Zostrix™ (RodlenLaboratories). These over-the-counter preparations can be purchasedwidely without a prescription and are used topically by consumers torelieve pain with variable and often inadequate results in conditionssuch as osteoarthritis, shingles (herpes zoster), psoriasis and diabeticneuropathy.

In addition to relieving pain, capsaicin triggers the body to increaseblood flow to promote natural healing on the skin surface and within theepidermal layers. This is especially important for healing injuries andenvironmental damage from pollution, sun and winter weather. Capsaicinis also a powerful anti-microbial that destroys bacteria in clogged skinpores and hair follicles.

Topical capsaicin has been used in skin and scalp care products thattarget a variety of conditions including acne, dermatitis, eczema,psoriasis and even dandruff. Capsaicin can stop itching when topicallyapplied. Known in the medical world as pruritus, itching is both asymptom and a cause of many skin ailments. The more a person itches, themore they scratch and the worse their condition becomes. Unfortunately,many skin and scalp conditions cause itching that leads to a chroniccycle of sick skin. From bug bites to eczema, the key to fast healing isto stop the itch so the condition can heal naturally, and capsaicin is aknown natural substance that can effectively do this.

Capsaicin mediated effects include: (i) activation of nociceptors inperipheral tissues; (ii) eventual desensitization of peripheralnociceptors to one or more stimulus modalities: (iii) cellulardegeneration of sensitive A-delta and C-fiber afferents; (iv) activationof neuronal proteases; (v) blockage of axonal transport; and (vi) thedecrease of the absolute number of nociceptive fibers without affectingthe number of non-nociceptive fibers.

The use of capsaicin is known for the treatment of a number of paindisorders. Accordingly, topical preparations of capsaicin find use as atopical therapy for a variety of skin disorders that involve pain anditching, such as postherpetic neuralgia, diabetic neuropathy, pruritus,psoriasis, cluster headache, postmastectomy pain syndrome, rhinopathy,oral mucositis, cutaneous allergy, detrusor hyperreflexia, loinpain/hematuria syndrome, neck pain, amputation stump pain, reflexsympathetic dystrophy, pain due to skin tumor and arthritis includingrheumatoid arthritis, osteoarthritis, diabetic neuropathy, psoriasis,pruritus (itching), cluster headache, post-surgical pain, oral pain, andpain caused by injury, amongst others. (Martin Hautkappe et al., Reviewof the Effectiveness of Capsaicin for Painful Cutaneous Disorders andNeural Dysfunction, Clin. J. Pain. 14:97-106, 1998).

Capsaicin is used in topical ointments and creams to relieve minor achesand pains of muscles and joints. Capsaicin is also available in largeadhesive bandages that can be applied to the back. Concentrations ofcapsaicin are typically between 0.025 wt. % and 0.075 wt. %.

One approach toward minimizing adverse effects and accelerating the rateof analgesia has been to topically apply a higher capsaicinconcentration as practiced by the Qutenza® (capsaicin) 8% patch underregional anesthesia. Application of the Qutenza® (capsaicin) 8% patchprovides for sustained analgesia lasting 1 to 8 weeks in cases ofcomplex regional pain syndrome and neuropathic pain (Robbins et al.Treatment of intractable pain with topical large-dose capsaicin:preliminary report. Anesth. Analg. 1998; 86:579-583). When topical localanesthetics were applied with 1% topical capsaicin, no alteration inpain produced by the capsaicin was observed in healthy subjectsindicating that this co-treatment approach was not sufficient to blockthe pain induced by capsaicin (Fuchs et al., Secondary hyperalgesiapersists in capsaicin desensitized skin. Pain 2000; 84: 141.)

Topical Analgesics

The primary use of a topical analgesic is to relieve the pain such asthat associated with arthritis as well as muscle aches and pains causedby sports injuries or physical work. One benefit of topical painrelievers is that they can be applied directly to the site of the pain,so there is minimal systemic distribution of the pain relieverthroughout the body. This localized application and associated actionminimizes the potential for systemic side effects. In addition, the painrelieving action of topical analgesics is faster than most oral formsbecause it is applied directly onto the painful area whereas oralanalgesics need to be digested, absorbed in the gastrointestinal tract,survive first-pass metabolism in the liver and then be transportedthroughout the body.

Ingredients possessing analgesic and other desirable therapeuticproperties include eugenol, thymol and several essential oils. Eugenol,a component of clove oil and some essential oils, has analgesic,anti-inflammatory, and antibacterial effects. Eugenol can also be mixedwith other pain reducing products to increase the pain relief.

Thymol is an essential oil found in several species of thyme and oreganoplants that contains significant antibacterial, antifungal, antiseptic,analgesic and antioxidant properties.

NSAIDs

NSAIDs decrease pain, inflammation, and fever by blocking cyclooxygenase(COX) enzymes. Understanding of the pharmacology of NSAIDs continues toevolve, but it is now thought that most NSAIDs block three different COXisoenzymes, known as COX-1, COX-2, and COX-3. COX-1 protects the liningof the stomach from acid. COX-2 is found in joint and muscle, andmediates effects on pain and inflammation. By blocking COX-2, NSAIDsreduce pain compared to placebo in patients with arthritis, low backpain, minor injuries, and soft tissue rheumatism. However, NSAIDs thatalso block the COX-1 enzyme (also called “nonselective NSAIDs”) cancause gastrointestinal bleeding.

Clinical trials have demonstrated that topical NSAIDs have a bettersafety profile than oral NSAIDs. Adverse effects secondary to topicalNSAID use occurs in about 10 to 15% of patients and are primarilycutaneous (rash and pruritus where the topical NSAID was applied).Gastrointestinal adverse drug reactions are rare with topical NSAIDs,compared with a 15% incidence reported for oral NSAIDs. Hayneman, C. etal. Oral versus topical NSAIDs in rheumatic diseases: a comparison,Drugs, pgs. 555-74, September, 2000.

Several topical formulations combine NSAIDS, primarily diclofenac salts,with capsaicin. TABLE 1 below contains a listing of several of theseformulations.

TABLE 1 Topical Formulations Containing Capsaicin & Diclofenac SaltsITEM TRADE NO. NAME ACTIVE INGREDIENTS COMPANY 1 Topac Gel; Topical;Capsaicin 0.025%; Abbott Fast Diclofenac Sodium 1%; Menthol 5%; MethylSalicylate 5% 2 Voveran Gel; Topical; Capsaicin 0.025%; NovartisThermagel Diclofenac Sodium 1%; Menthol 5%; Methyl Salicylate 5% 3 XidolGel; Topical; Capsaicin 0.025%; Dewcare Gel Diclofenac Diethylamine1.16%; Concept Linseed Oil 3%; Menthol 5%; Methyl Salicylate 10% 4Diclomax Gel; Topical; Capsaicin 0.025%; Torrent Power DiclofenacDiethylamine 1.16%; Pharmaceuticals Linseed Oil 3%; Menthol 5%; MethylSalicylate 10% 5 Divexx Gel; topical; Capsaicin 0.022%; Zuventus GelDiclofenac Sodium 1%; Menthol Healthcare 5%; Methyl Salicylate 10%

Gellert Joint Cream has a capsaicin concentration of 0.17% and contains74% water. The current aqueous capsaicin formulations are limited byrelatively low capsaicin concentrations.

U.S. Pat. No. 4,424,205 discloses a variety of hydroxyphenylacetamideshaving analgesic and anti-irritant properties.

U.S. Pat. No. 4,486,450 discloses a method and composition of treatingpsoriatic skin in which capsaicin is applied topically to the psoriaticskin in a pharmaceutically acceptable carrier wherein capsaicin ispresent in therapeutically acceptable concentrations of between about0.01 and about 1 percent by weight. Subsequent exposure of the treatedpsoriatic skin to ultraviolet light in small doses aids treatment.

U.S. Pat. No. 4,997,853 discloses a method and composition for treatingsuperficial pain syndromes, which incorporates capsaicin into apharmaceutically acceptable carrier, and adding to this composition alocal anesthetic such as lidocaine or benzocaine. The compositioncontaining the anesthetic is then applied to the site of the pain. Avariation on the treatment includes initial treatment with thecomposition containing the local anesthetic until the patient has becomedesensitized to the presence of capsaicin and subsequent treatment witha composition omitting the local anesthetic.

U.S. Pat. No. 5,134,166 discloses methods and compositions for treatingcertain allergy related condition and headaches using capsaicin insolution or suspension combined with a selected anesthetic, topicalsteroid or antihistamine.

U.S. Pat. No. 5,178,879 discloses clear, water-washable, non-greasy gelsuseful for topical pain relief containing capsaicin, water, alcohol anda carboxypoly-methylene emulsifier. A method of preparing the gels isalso disclosed.

U.S. Pat. No. 5,560,910 discloses compositions and methods that areuseful for topically treating inflammation caused by a wide variety ofdiseases. The compositions comprise an effective amount of a proteolyticenzyme, such as bromelain, in combination with capsaicin in apharmaceutically acceptable carrier.

U.S. Pat. No. 5,910,512 discloses a water-based topical analgesic andmethod of application wherein the analgesic contains capsicum, capsicumoleoresin and/or capsaicin. This analgesic is applied to the skin toprovide relief for rheumatoid arthritis, osteoarthritis, and the like.

U.S. Pat. No. 5,962,532 discloses a method of providing pain reliefcomprising administering an anesthetic along with injecting acomposition of capsaicin.

U.S. Pat. No. 6,239,180 discloses a transdermal application of capsaicinin a concentration from greater than about 5 wt. % to about 10 wt. % fortreating neuropathic pain. An anesthetic is initially administered tominimize the burning side effects from subsequent capsaicin application.

U.S. Pat. No. 6,348,501 discloses a lotion for treating the symptoms ofarthritis using capsaicin and an analgesic along with a method formaking such formulations.

U.S. Pat. No. 6,573,302 discloses a cream comprising: a topical carrierwherein the topical carrier comprises a member selected from the groupcomprising lavender oil, myristal myristate, and other preservatives inaddition to hypericum perforatum arnica montana capric acid; and 0.01 to1.0 wt. % capsaicin; 2 to 10 wt. % of an encapsulation agent selectedfrom the group comprising colloidal oatmeal hydrogenated lecithin,dipotassium glycyrlhizinate and combinations thereof; esters of aminoacid; a light scattering element having a particle size up to 100 nm.;and a histidine.

U.S. Pat. No. 6,593,370 discloses a topical capsaicin preparation forthe treatment of painful cutaneous disorders and neural dysfunction. Thepreparation contains a nonionic, amphoteric or cationic surfactant in anamount effective to eliminate or substantially ameliorate burning paincaused by capsaicin.

U.S. Pat. No. 6,689,399 provides an anti-inflammatory composition fortreatment of joint and muscle pain through transdermal delivery of acapsacinoid in conjunction with glucosamine. The ingredients of thecomposition of the present invention, namely, a capsacinoid incombination with a primary amine, such as glucosamine, at a highconcentration.

US Patent Application 2005/0090557 relates to compositions of a TRPV1agonist such as capsaicin, and a solvent system such as a penetrationenhancer.

U.S. Patent Application 2006/0100272 discloses compositions and methodsfor the treatment of pain, and neuropathic pain in particular. Theformulations are eutectic mixtures of a capsaicinoid and a localanesthetic agent and/or an anti-pruritic agent.

US Patent Application 2006/0148903 relates to a method of treating postsurgical pain comprising administering at the surgical site, a dose ofcapsaicinoid gel.

U.S. Pat. No. 7,282,224 discloses a pain relief composition comprisingan effective amount of a nerve inhibiting component, includingcapsaicin, a capsaicinoid or a capsaicin analogue, which numbs orinhibits the nerve endings that signal pain, in combination with atleast one of the following: an effective amount of an inflammationcontrol component which is designed to reduce immediate pain anddiscourage future pain in the joints and muscles; an effective amount ofa cooling component; an effective amount of a heat minimizing orblocking component; an effective amount of a circulation increasingcomponent which effectuates better penetration of the actives to theskin and nerves; and an effective amount of a soothing andanti-inflammatory complex for the joints and/or muscles comprisingglucosamine sulfate or HCl, zingiber officiniale (ginger root) extract,methyl sulfonylmethane (MSM), Polygonum cuspidatum.

U.S. Pat. No. 7,632,519 discloses a variety of TRPV1 agonist compounds(capsaicinoids and their related esters) and formulations thereof.

U.S. Pat. No. 7,771,760 discloses topical oils of capsacinoidscomprising a capsaicinoid, a solvent capable of solubilizing thecapsaicinoid, and a capsaicinoid crystallization inhibitor.

U.S. Pat. No. 7,943,166 relates to a method and liquid solvent system ofpenetration enhancers from 10% (w/v) to about 30% (w/v) of a TRPV1agonist, such as capsaicin, where a single topical application of theliquid formulation results in pain relief for at least two weeks.

U.S. Pat. No. 7,943,666 discloses formulations of ester derivatives ofcapsaicin and ester derivatives of myristoleic acid. These derivativesare capable of reverting to the active parent compound followingenzymatic or chemical hydrolysis. These derivatives have a higherlipophilicity, lipid solubility and less irritation to the skin than theparent compound, and hence are better able to be incorporated intocertain pharmaceutical formulations, including cream and ointmentpharmaceutical formulations. The disclosed pharmaceutical compositionsare useful for pain management in mammals in vivo and have beencontemplated to be used in the treatment of various pains in humans.

U.S. Pat. No. 8,703,741 relates to the use of vanilloid receptor agonisttogether with a glycosaminoglycan or proteoglycan for producing an agentfor treating pain.

U.S. Pat. No. 8,802,736 relates to topical compositions of TRPV1agonists.

Despite the advancements in the art, there remains a need for moreeffective pain-relieving capsaicinoid formulations.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a topical pain reliefcomposition that provides long-term pain relief without loss ofsensation in the area treated.

It is an object of the invention to provide topical compositions ofTRPV1 selective agonists such as capsaicin and other related compoundsin preparations which eliminate or substantially ameliorates initialburning/stinging pain caused by the TRPV1 selective agonist compoundobserved following topical administration thereby making the preparationtolerable following initial and long-term use.

It is an object of the invention to provide topical TRPV1 selectiveagonist containing compositions such as capsaicin formulations for usein the treatment of joint pain, muscle pain, tendonitis, and for certainforms of localized neuropathic pains that are not amenable to treatmentwith currently marketed topical preparations, and do not have the sideeffects of systemic treatments.

It would be advantageous to provide methods and compositions containingcompositions such as capsaicin or analogues thereof, at therapeuticallyeffective concentrations to cause a pain relieving effect without theside effects normally associated with the use of capsaicinoids.

It is therefore an object of the present invention to provide methodsfor administering capsaicin or capsaicin analogues topically at highconcentrations to achieve a prolonged pain reduction effect but withoutthe severe burning sensation that occurs following topical application.

It is yet another object of the present invention to providecompositions containing agents to complement the remedial properties ofcapsaicin, or related compounds, for the treatment of pain of the jointsand muscles and other medical conditions, where the agents areconveniently administered with the capsaicin.

It is yet another object of the present invention to provide acomposition and method for topically treating pain and inflammation thatis safe and effective and does not have the side effects of opioids orconventional NSAIDS.

It is another object of this invention to provide solvent systems thatsolubilize appreciable concentrations of the relatively aqueousinsoluble TRPV1 selective agonists (such as capsaicin) to producecompositions such that solvent systems contains analgesic andanti-inflammatory ingredients that rapidly penetrate the layers of skinto mitigate the stinging and burning pain resulting from the topicalapplication of the significant capsaicin concentrations, and that canimprove storage stability.

Other objects and advantages of the present invention will be apparentfrom a review of the following specification.

SUMMARY OF THE INVENTION

The invention relates to a composition comprising:

i) 0.075-20% by weight of a capsaicinoid,

ii) an extended release agent to slow the release of said capsaicinoidfrom said composition upon administration of said composition to amammal, and

iii) a surfactant,

wherein said composition reduces or eliminates the burning and stingingcreated by said capsaicinoid upon topical administration.

In another embodiment, the invention is a composition comprising:

i) 0.075-20% by weight of a capsaicinoid,

ii) 70-99.925% by weight of an aqueous vehicle comprising a nonionicsurfactant (for dissolving the capsaicinoid or for forming an emulsion)or for maintaining a stable solution, and an extended release agent toslow the release of said capsaicinoid from said aqueous composition upontopical administration of said composition in a mammal, wherein saidaqueous vehicle reduces or eliminates the burning and stinging createdby said capsaicinoid upon topical administration.

In an advantageous embodiment, the capsaicinoid is 2-30% by weightcapsaicinoid, and the extended release agent is hyaluronic acid, at0.5-1.5° % by weight of the composition. Advantageously, the hyaluronicacid is a mixture of both low molecular weight hyaluronic acid and highmolecular weight hyaluronic acid. In another embodiment, the extendedrelease agent is collagen or elastin.

In other advantageous embodiments, the invention includes asolvent/penetration enhancer such as DGME, ethanol and/or propyleneglycol, an analgesic or anesthetic agent such as methyl salicylate,camphor, menthol, icilin, eucalyptol and/or phenol; or ananti-inflammatory agent, such as a flavonoid, a steroid, and/or anNSAID.

Advantageous embodiments of the compositions of the invention include.

a composition comprising:

-   -   i) a capsaicinoid,    -   ii) an extended release agent,    -   iii) a surfactant, and    -   iv) a penetration enhancer;        a composition comprising:        i) 0.2-20% by weight of capsaicinoid,        ii) 0.1-0.5% by weight of said extended release agent,        iii) 0.5-15% by weight nonionic surfactant;        a composition comprising:    -   i) 2-20% by weight of capsaicinoid,    -   ii) 0.2-0.5% by weight of hyaluronic acid, and    -   iii) 2-15% by weight nonionic surfactant; and        a composition comprising:    -   i) 0.20-20% by weight of a capsaicinoid,    -   ii) 0.1-0.5% by weight hyaluronic acid,    -   iii) 2-15% by weight PS 80 or polyoxy 40 hydrogenated castor        oil, and    -   iv) 1-40% by weight penetration enhancer.

The invention also includes:

a method of formulating an aqueous capsaicinoid formulation comprising:

i) dissolving a capsaicinoid in a surfactant to form a solution, and

ii) adding an aqueous solution of hyaluronic acid to the solution ofstep i);

a method of producing an aqueous topical formulation of capsaicincomprising:

i) mixing a capsaicinoid, a surfactant and a penetration enhancer, and

ii) adding an aqueous solution of hyaluronic acid to the product of stepi); and

a method of producing an aqueous topical formulation of capsaicincomprising:

i) mixing a capsaicinoid, and a penetration enhancer, and

ii) adding an aqueous solution of hyaluronic acid to the product of stepi),

iii) adding a surfactant to the product of step ii).

The invention also relates to methods of making and using compositionsfor the treatment of pain such as joint pain (e.g. arthritis pain),muscle pain, as well as treating a variety of other medical conditions.A method of treating itching or fingernail or toenail fungus in a mammalis also included. Typically, administration is topical application tothe affected area.

Methods of treating pain in a mammal (e.g. human) comprise topicallyadministering the compositions of the invention, and include methods ofreducing the density of nociceptor nerve fibers in the dermis andepidermis of a selected region of a mammal, comprising administering thecomposition of the invention to said region, e.g. where the density offunctional nociceptive nerve fibers is decreased by at least 20%, 30%,40% or 50% after topically administering the composition.

The invention includes methods of treating a capsaicin responsivecondition such as pain including neuropathic pain, inflammatoryhyperalgia, vulvodynia, interstitial cystitis, rhinitis, burning mouthsyndrome, oral mucositis, herpes, dermatitis, pruritis, tinnitus,psoriasis, or headaches, with the compositions of the invention.

Lastly, the invention also relates to kits comprising the liquidformulation of the invention and a non-occlusive applicator device. Inanother embodiment the kit further comprises a cleaning solution forremoval of residual agonist.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides topical pharmaceutical compositions containing atherapeutically effective amount of a TRPV1 agonist, an extended releaseagent such as hyaluronic acid, a surfactant, and optionally, one or morepenetration enhancers. The pharmaceutical composition is in a formsuitable for topical administration to a mammal, typically human. Theconcentration of capsaicin is typically greater than 0.02 wt. % and lessthan 20 wt. % of the formulation.

In one embodiment, the composition comprises a capsaicinoid, hyaluronicacid, a surfactant and one or more penetration enhancers, where saidsurfactant and one or more penetration enhancers, taken together,constitute at least about 20% by wt., at least about 50% by wt., and upto 70% by wt. of the formulation.

Penetration enhancers can be an ether, or an alcohol. The formulationcan contain one or more penetration enhancers selected from the groupconsisting of propylene glycol, ethyl alcohol, diethylene glycolmonomethyl ether (DGME), and dimethyl sulfoxide, and can contain anonionic surfactant e.g.s. PS-80 and polyoxy-40 Hydrogenated Castor Oil.

In an advantageous embodiment, a 0.4 wt. % hyaluronic acid watersolution composed of a mixture containing 70 wt. % hyaluronic acid witha molecular weight ˜11 kDaltons and 30 wt. % hyaluronic acid with amolecular weight of ˜1,000 kDaltons was added to an alcohol mixturesolution containing 0.25 wt. % to 10 wt. % capsaicin dissolved insolublizing and penetrating agents consisting of ethyl alcohol,propylene glycol and PS80 and/or polyoxy 40 hydrogenated castor oil(balance water). The mixture resulted in an optically crystal clear andmoderately viscous solution. Adjusting the relative percentages of thehyaluronic acid molecular weights and surfactant composition resulted invariation of viscosity of the mixture.

Capsaicin formulations of 0.25% wt. % to 10 wt. % as described in theforegoing paragraphs was applied to knees, arms of several subjects viaa 3.7 ml roller-ball vial (See Examples). The applied liquid film driedrapidly and minimal discomfort from burning and stinging wasexperienced. The formulations were relatively odor free.

Surprisingly, using the methods and compositions of the invention inhumans results in less pain or discomfort than administration ofconventional capsaicin formulations containing much lower concentrationsof capsaicin. Example 2 below shows that, 0.25 wt. % capsaicin liquidformulation produced less burning and stinging than a common liquidcapsaicin formulation containing 0.15 wt. % capsaicin.

The invention provides methods for administration of a TRPV1 agonistsuch as capsaicin, at a concentration of greater than 1% by wt., greaterthan 2%, greater than 5%, greater than 8%, or even greater than 10% bywt., without significant burning and stinging.

Compositions of the Invention

The invention relates to compositions, advantageously liquid aqueoussolutions, comprising a TRPV1 selective agonist, and a surfactantcapable of solubilizing said TRPV1 selective agonist, wherein saidcomposition has an amount of TRPV1 selective agonist sufficient todecrease the density of functional nociceptive nerve fibers when saidcomposition is applied topically, and said composition has an amount ofa extended release agent and surfactant sufficient to eliminate orreduce the burning and/or stinging sensation or erythema created by thetopical administration of the TRPV1 selective agonist. The liquidsolution of the invention is advantageously an aqueous solution.

The TRPV1 selective agonists, hyaluronic acid or other extended releaseagents, surfactants, and excipients suitable for use in thepharmaceutical compositions of the present invention, are those whichare pharmaceutically acceptable when applied to human skin, i.e. havingacceptable toxicity at the levels used. All components of theformulations of the invention are USP grade. In a preferred embodimentof the invention, the compositions are manufactured in full compliancewith GMP regulations of the U.S. FDA.

In one embodiment, the amount of TRPV1 selective agonist sufficient todecrease the density of functional nociceptive nerve fibers by at least20%, or at least 50%, after topical application. In another embodimentthe composition is 0.20-30% by weight of the TRPV1 selective agonist.The TRPV1 selective agonist can be a vanilloid, or in an advantageousembodiment, a capsaicinoid such as capsaicin.

When combined with ingredients disclosed herein, the amount of TRPV1selective agonist, e.g. a capsaicinoid (e.g. trans-capsaicin) in thetopical preparation can be from 0.075-30 wt. %, 0.2 wt. % to 30 wt. %,between 1 wt. % and 20 wt. %, e.g. 1 wt. %, 5 wt. %, 10 wt. %, and 20wt. %.

The capsaicinoid is prepared for topical application by beingincorporated into a pharmaceutically and physiologically acceptableaqueous vehicle for administration with diminished burning sensationupon application. The present invention is directed to the topicaladministration of capsaicin into discrete localized areas for thetreatment and lessening of pain. Significant advantages result from theapplication of milligram quantities of capsaicin in order to producetherapeutic results through alteration of sensory nerve function(TRPV-1) in a limited area.

The invention relates to compositions, typically liquid solutionpharmaceutical formulations, of a TRPV1 selective agonist (i.e. actingas specific agonist for TRPV1 as capsaicin does) such as capsaicinoid ora capsaicin analogue, primarily for the treatment of pain. Thecompositions include one or more extended release agents and asurfactant which reduce or eliminate the burning or stinging pain causedby administration of the TRPV1 selective agonist, thereby making theTRPV selective agonist formulation administration tolerable, includingin long-term administration. The present application discloses thediscovery that a TRPV1 selective agonist containing topical compositionis very effective in treating pain in humans and causes significantlyless burning pain at the site of the application, when administered witha extended release agent and a surfactant, than the same compositionwithout such components.

The present invention provides the long lasting pain relief afforded bythe TRPV1 selective agonist, e.g. capsaicin, without the same severityof concentration-dependent capsaicin side effects (e.g. stinging andburning) associated with prior art capsaicin formulations. Theformulations can provide pain relief for periods of weeks to monthsdependent upon disease state and severity. Importantly, unlikeanesthetics and opiods, the formulations of the present invention do notdiminish or eliminate tactile sensation in the skin onto which theformulation has been topically applied.

The topical formulations, particularly for the treatment of pain,contain higher levels of TRPV1 selective agonists such as capsaicin,than normally used. The subject formulations do not have the discomfortand burning associated with capsaicin formulations of the prior art. Theformulations of the TRPV1 selective agonist can includeanti-inflammatory, and other additives that contribute to pain reliefand the therapeutic treatment of pathological conditions such asarthritis pain, osteoarthritis, joint disorders, muscular pain,neuropathic pain, neck and back pain, shingles, cluster headaches andother disease or health-related conditions.

The subject invention relates to pharmaceutical topical compositions fordelivery of significant quantities of a TRPV1 selective agonist compoundsuch as capsaicin or related compounds via the skin. The components ofthe composition other than the TRPV1 selective agonist compound areincluded to reduce or eliminate the burning sensation associated withadministration of the TRPV1 selective agonist compound as well as toenhance skin penetration of said TRPV1 selective agonist compound. Theadditional components are typically hyaluronic acid and a nonionicsurfactant such as PS 80, which are generally accepted as safe.

It has been discovered that incorporation of a sufficient quantity ofthese ingredients into the capsaicin preparations forms a mixture forthe topical treatment of pain such that the initial burning/stingingpain resulting from capsaicin is eliminated or ameliorated. Waterconcentrations are typically 30-60 wt % or 40-60 wt % of thepreparations and can exceed 50% or even 55 wt % of the formulations.

It has been demonstrated that these ingredients reduce theburning/stinging sensation produced following topical application of aTRPV1 selective agonist compounds such as capsaicin. The compositions ofthe invention include appreciable quantities of hyaluronic acid and asurfactant, and optionally phenol which minimizes the burning/stingingsensation produced following topical application capsaicin. Componentscan also be added which enhance the penetration of the capsaicin intothe viable layers of the skin and into subcutaneous tissues.

Accordingly, the present invention provides topical preparationscomprising an amount of a TRPV1 selective agonist such as capsaicineffective in initial and long-term or repeated administration to reducepain associated with certain cutaneous disorders and neuraldysfunctions.

The components of the formulations of the invention are discussed below.

TRPV1 Selective Compounds including Capsaicinoids

For a general discussion of TRPV1 agonists including capsaicinoids ofthe invention, see US patent application 2008/0262091, and commonlyowned U.S. Ser. No. 13/609,100, each of which is hereby incorporated byreference in its entirety. The term “capsaicinoid” as used hereinincludes capsaicin, a capsaicinoid other that capsaicin, i.e.dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin,homocapsaicin, and nonivamide, and a mixture of capsaicin with one ormore other capsaicinoids. The amount of drug used being based on atherapeutically dose to a dose of capsaicin. Capsaicin is practicallyinsoluble in water, but freely soluble in ethyl alcohol, diethyleneglycol monoethyl ether (DGME), dimethyl sulfoxide (DMSO) and propyleneglycol. Capsaicin is a lipophilic white crystalline powder; meltingpoint 60-65 degrees C.

Alternatively, a “capsaicin analogue” such as resiniferatoxin, can beadministered in place of part or all of the capsaicinoid. The amount ofanalogue administered being the therapeutically equivalent dose ofcapsaicin-see US patent application 2008/0262091, hereby incorporated byreference in its entirety. In another embodiment, a TRPV1 agonist otherthan a capsaicinoid, or capsaicin analogue, is utilized in theformulations and methods of the invention.

According to the present invention, the pain relief compositioncomprises a therapeutically effective amount of a nerve-inhibitingcomponent—a TRPV1 selective agonist, which inhibits the nerve endingsthat signal pain. The TRPV1 selective agonist component is typically avanilloid, a capsaicinoid, more specifically capsaicin, nonivamide orother capsaicin analogue, or a mixture thereof.

TRPV1 selective agonist compounds of the subject invention include thenatural capsaicinoids (Capsaicin Oleoresin), and synthetic (Nonivamide)forms, as well as analogues of capsaicin. Capsaicin is known by thechemical name N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide.Capsaicin is the main capsaicinoid (typically 69%) in chili peppers,followed by dihydrocapsaicin (typically 22%) and norihydrocapsaicin(typically 7%). Nonivamide is found in trace amounts in chili peppers.

TABLE 2 CAPSAICIN & CAPSAICINOID PROPERTIES Capsai- Natural Scovillecinoid Relative Heat Molecular Name Abbr. MW Amount Units FormulaChemical Structure Capsaicin C 305 69%  16 × 10⁶ C₁₈H₂₇NO₃

Dihydro- capsaicin DHC 307 22%  15 × 10⁶ C₁₈H₂₉NO₃

Nordihydro- capsaicin NDHC 293  7% 9.1 × 10⁶ C₁₇H₂₇NO₃

Homo- dihydro- capsaicin HDHC 321  1% 8.6 × 10⁶ C₁₉H₃₁NO₃

Homo- capsaicin HC 319  1% 8.6 × 10⁶ C₁₉H₂₉NO₃

Nonivamide PAVA 293 ⁽¹⁾0.25% 9.2 × 10⁶ C₁₇H₂₇NO₃

⁽¹⁾Constant et al. J. Nat. Prod. 1996, 59, 425-426

As noted above in TABLE 2, capsaicin and several related compounds arecalled capsaicinoids. Nonivamide, the vanillylamide of n-nonanoic acid(also PAVA) is used as a reference substance for determining therelative pungency of capsaicinoids as well as being used as a foodadditive to add pungency.

Capsaicin and dihydrocapsaicin together make up 80-90% of thecapsaicinoids found in chili peppers. The different capsaicinoidcompounds have slight structural variations in the hydrocarbon tail,changing their ability to bind to the nerve receptors and their abilityto penetrate layers of receptors on the tongue, mouth, and throat.

Capsaicinoids are very similar in structure, varying only by the lengthof along hydrocarbon portion (that is, a portion containing only carbonand hydrogen atoms), and by the presence or absence of onecarbon-to-carbon double bond in that hydrocarbon portion (carbon-carbondouble bonds). Both the naturally occurring capsaicin and the syntheticversions that differ slightly in their alkyl chain, have similarpharmacological effects.

Nonivamide is present in chili peppers but is commonly manufacturedsynthetically. It is more heat-stable than capsaicin. Ointments sold torelieve arthritis and muscle pain often contain nonivamide. Applicationof the ointment on the skin is claimed to result in a warm to burningsensation and pain relief for several hours.

Resiniferatoxin (RTX) is a very potent capsaicin analogue. Other TRPV1selective agonists include anandamide, and NADA. Many additionalagonists are disclosed in U.S. Pat. Nos. 7,943,166 and 7,632,519, eachof which is hereby incorporated by reference in its entirety. Somecapsaicin analogues are described in U.S. Pat. No. 5,962,532, herebyincorporated by reference in its entirety.

The formulations of the invention typically include 0.075-30% by weight,0.2-30%, or 2-20%, 2-10% or 5-15% of a capsaicinoid (e.g. capsaicin), orrelated compounds. When the TRPV1 selective agonist is other thancapsaicin, since potency can vary, the amount of agonist in theformulation is that amount which achieves the same results achieved bythe weight percent ranges noted herein for capsaicin.

Extended Release Agents

It has been found that inclusion of certain compounds which slow therelease of a capsaicinoid from the formulation (causing extendedrelease), result in diminished burning and stinging effects.Advantageously, the extended release agent will release saidcapsaicinoid over a period of greater than 15 minutes, 30 minutes, 1hour, or greater than 4 hours. In one embodiment, the capsaicinoid isreleased over a period greater than a week. Typically a higher dose willbe released over a longer time period. In one embodiment of theinvention, the extended release agent is not a glycosaminoglycan or aproteoglycan.

Hyaluronic Acid

The molecular weight of hyaluronic acid (HA) of the inventionadvantageously ranges from 3 kDaltons to 1,000 kDaltons. In certainembodiments, the formulations can include “high” molecular weighthyaluronic acid of greater than 800 kDaltons, i.e. 1000, 2000, 3000,4000 or 5000 kDaltons. In certain embodiments, the formulations caninclude “low” molecular weight hyaluronic acid of less than 200 kDalton,advantageously less than 20 kDalton, more advantageously less than 15kDalton. The hyaluronic acid component of the solubilized capsaicinformulations forms a polysaccharide network within the aqueous solutionthat contributes to a delayed and prolonged release of capsaicin thuscontributing to minimizing the discomfort from the application ofcapsaicinoid.

HA has been extensively utilized in cosmetic products because of itsviscoelastic properties and excellent biocompatibility. Application ofHA containing cosmetic products to the skin is reported to moisturizeand restore elasticity thereby achieving an anti-wrinkle effect.

The high solubilization of capsaicin using the nonionic surfactants PS80 and/or Cremophor RH 40, together with hyaluronic acid, a substancethat is naturally present in the human body that occurs in varioustissues (skin, synovial fluids of joints and connective tissues),contribute to ameliorating the burning and stinging associated withcapsaicin formulations. In an advantageous embodiment, <0.5 wt. %hyaluronic acid and its salts (0.35 wt. % HA<50 kDaltons and ˜0.15 wt. %HA ranging from 800 to 1,200 kDaltons), significantly contributes to areduction in the capsaicin associated burning and stinging reaction. Thehigh MW hyaluronic acid used in the Examples herein had an averagemolecular weight of 1000 kDaltons. While not wishing to be bound bytheory, it is believed that the addition of the hyaluronic acidcomponent to the capsaicin forms a polysaccharide network within theaqueous solution that causes capsaicin to be released more slowly in acontrolled manner that results in a lessening of the burning andstinging pain.

The physiological function of the stratum corneum, the outermost andnon-viable layer of the skin, is to act as a protective barrier for thebody and as such it is particularly effective at preventing thepermeation of hydrophilic molecules including some drugs into deeperskin layers, where viable cells are located. Low molecular weight (MW)HA provides better penetration abilities than higher MW HA and,accordingly, influenced the expression of many genes including thosecontributing to keratinocyte differentiation and formation ofintercellular tight junction complexes which are reported to be reducedin aged and photo-damaged skin. These different molecular properties ofhigh and low MW HA generated different in-vivo effects with pronouncedmoisturization and elasticity properties shown for high MW HA and markedreduction of wrinkles demonstrated for low MW HAs. The increasedactivity at decreasing molecular weight can be explained by the moreefficient skin penetration of the smaller HA molecules. (Farwick, M., etal. Low Molecular Weight Hyaluronic Acid: Its Effects on Epidermal Gene.Expression and Skin Aging, International Journal for Applied Science.)

Low molecular weight hyaluronic acid can penetrate the epidermal layerof the skin and seep into a deeper region, where it supplements thewater loss and helps restore the natural cell regenerative qualities inskin. The high MW hyaluronic acid works on the epidermal level andoffers a protective effect, hydrating and healing the protective barrierof the skin. This provides a smoother skin surface. Combining the lowand high HA molecular weights utilizes the unique characteristics andbenefits of the two types of HA to reduce the burning and stingingeffects of capsaicinoids.

Advantages of HA for dermal administration of capsaicin are: surfacehydration and film formation enhance the permeability of the skin totopical drugs, it promotes drug retention and localization in theepidermis; and it exerts an anti-inflammatory action (medium andhigh-molecular-weight HA). In one embodiment of the invention, thehyaluronic acid is in the form of a cross-linked hydrogel.

Collagen and Elastin

Collagen is the main structural protein of the various connectivetissues in animals. As the main component of connective tissue, it isthe most abundant protein in mammals, making up from 25% to 35% of thewhole-body protein content. Collagen, in the form of elongated fibrils,is mostly found in fibrous tissues such as tendons, ligaments and skin,and is also abundant in corneas, cartilage, bones, blood vessels, thegut, and intervertebral discs.

Elastin is a protein in connective tissue that is elastic and allowsmany tissues in the body to resume their shape after stretching orcontracting. Elastin helps skin to return to its original position whenit is poked or pinched. Elastin is also an important load-bearing tissuein the bodies of vertebrates and used in places where mechanical energyis required to be stored.

Collagen and/or elastin with a capsaicinoid is advantageous in thetreatment of pain including OA pain. The addition of the collagen and/orelastin component to a solubilized capsaicin formulation forms a proteinnetwork within the aqueous solution that contributes to a delayed andprolonged release of capsaicin thus contributing to minimizing theburning discomfort from either topical application or injection ofcapsaicin. Additionally, upon injection with a capsaicinoid thesenaturally occurring high molecular weight proteins function to controlthe rate of capsaicin release to the nerves to reduce burning, providelubrication to the sliding bone surfaces as well as provide buildingmaterials for bone cartilage repair. Addition of hyaluronic acid tocapsaicinoid formulations containing either or both these naturallyoccurring high molecular weight proteins further optimizes tolerabilityand efficacy. In the compositions of the invention, the collagen orelastin must be in the form of a liquid or gel.

Bioresorbable Polymer Matrix

A bioresorbable polymer matrix, e.g. a cross-linked oxidized dextranhydrogel, can also be used in the formulations of the invention as theextended release agent. See U.S. Pat. No. 8,435,565 hereby incorporatedby reference in its entirety.

Surfactants

One or more surfactants, advantageously non ionic (e.g. polysorbatessuch as PS80, Cremophor® RH 40 (polyoxy 40 hydrogenated castor oil),sorbitan esters (Spans), poloxamers, cetyl alcohol, cetostearyl alcohol,polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, stearylalcohol etc.), can be also be added to the compositions of the inventionto solubilize the capsaicinoid and enhance the skin penetration of thecapsaicinoids. They can ameliorate the initial stinging pain caused bycapsaicin (or related compounds) in admixture with the pharmaceuticallyacceptable carrier ingredients for topical administration. Fatty acidester non-ionic surfactants that are utilized in pharmaceutical,cosmetics and foodstuffs are advantageous because of the compatibilitywith biological tissues.

A surfactant, such as a nonionic surfactant, e.g. PS 80 and/orCremophor® RH 40 (polyoxy 40 hydrogenated castor oil) (alternatively,Solute® HS 15), can be combined with hyaluronic acid and one or more ofthe pharmaceutically acceptable vehicles described herein so that thesurfactant serves as a wetting agent, solubilizer, and emulsifier andcontribute to minimizing the stinging or burning discomfort associatedwith capsaicinoid administration.

Further, surfactant/capsaicin (or other capsaicinoid(s)) concentratescan be formed for use in the formulations and methods of the inventionas described in commonly owned U.S. Pat. No. 8,637,569 herebyincorporated by reference in its entirety.

In one embodiment of the invention, a surfactant is not present in thecomposition. An example is where the capsaicinoid concentration is lessthan 0.25% by wt.

Examples of formulations of the invention with the surfactant PS 80 areshown below:

2%, 5%, and 10% CAPSAICIN-HA FORMULATIONS (Optically Clear Single PhaseFormulations) 2 wt. % 5 wt. % 10 wt. % INGREDIENTS HA-Cap HA-Cap HA-CapCAPSAICIN (Formosa) 2 5 10 POLYSORBATE 80 7 10 13 (Super Refined -Croda) ETHYL ALCOHOL 20 20 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 10 10METHYL ETHER (DGME) PROPYLENE GLYCOL 10 10 10 ⁽¹⁾HA (~1,000K Daltons)0.17 0.17 0.12 ⁽¹⁾HA SLMW (~20K Daltons) 0.33 0.33 0.25 ⁽¹⁾DISTILLEDWATER 50.50 44.50 36.63 TOTAL 100 100 100

Examples of formulations of the invention with the surfactant CremophorRH 40 are shown below:

HA-CAPSAICIN FORMULATIONS ¼% 2% 5% 10% 15% 20% Cap-HA Cap-HA Cap-HACap-HA Cap-HA Cap-HA INGREDIENTS (wt. %) (wt. %) (wt. %) (wt. %) (wt. %)(wt. %) CAPSAICIN (Formosa) 0.25 2 5 10 15 20 CREMOPHOR RH 40 5 7 10 1216 16 ETHYL ALCOHOL 20 20 20 20 20 20 (Grain Alcohol) ETHOXYDIGLYCOL 1010 10 10 10 10 (DGME) PROPYLENE GLYCOL 10 10 10 10 10 10 ⁽¹⁾ HYALURONICACID AQUEOUS 54.75 51 45 38 29 24 SOLUTION TOTAL 100 100 100 100 100 100Note: ⁽¹⁾ The Hyaluronic Acid Aqueous Solution contains 0.65 wt.%Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000KDaltons) and 99 wt. % Distilled Water.Agents that Enhance Skin Penetration

Diethylene glycol monoethyl ether (DGME) is a penetration enhancer (andsolvent) useful in the formulations of the invention. It is commerciallyavailable as Transcutol® (Gattefossé Corp., Paramus, N.J.). DGME is bothan effective solvent and penetrating agent for capsaicinoids. Otherpenetrating agents include propylene glycol, ethoxydiglycol, anddimethyl isosorbide, each known in the art of topical formulationdevelopment to enhance skin penetration.

Alcohols including ethyl alcohol, benzyl alcohol, glycerol, propanol,isopropyl alcohol, polyethylene glycol, polyethylene glycols, etc. canbe added to the formulations as effective capsaicin solubilizing andpenetrating agents. Addition of an alcohol results in compositions withlower viscosity and shorter drying times.

Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula(CH₃)₂SO. This colorless liquid is an important polar aprotic solventthat dissolves both polar and nonpolar compounds and is miscible in awide range of organic solvents as well as water. It penetrates the skinvery readily and has the unusual property that many individuals perceivea garlic-like taste in the mouth after contact of DMSO with the skin.

Analgesic Agents

The compositions of the subject invention also include an analgesicagent—one or more analgesics. As used herein, an “analgesic agent” is acompound or compounds which, when topically applied, reduces pain orburning sensation without loss of tactile sensation. The analgesicsagents of the invention do not include a capsaicinoid and do not includean opioid. Further, the analgesic agents do not include a topical localanesthetic, such as lidocaine (or procaine, amethocaine, cocainelidocaine (also known as Lignocaine), prilocaine, bupivacaine,levobupivacaine, ropivacaine, mepivacaine, dibucaine) in the TRPV1specific agonist containing formulations. These caine local anestheticshave not been effective in sufficiently moderating the burning effect ofcapsaicin when administered concomitantly with capsaicin topically; theyhave a slower onset of action relative to capsaicin. To reduce theburning sensation, these caine local anesthetics are typicallyadministered in advance of capsaicin attempting to elicit sufficientanesthetic action prior to the burning sensation associated withcapsaicin.

The present application includes the discovery that topical TRPV1selective agonist containing compositions have significantly lessburning pain at the site of the application when combined with topicalanalgesic and/or anesthetic agents (when compared to the samecomposition without analgesic and/or anesthetic agents), and areextremely effective in treating pain in mammals including humans. Asused herein, “topical” refers to administration of the composition to adefined area of the body such as a defined area of skin surface ormucous membrane.

Menthol

Menthol is an organic compound made synthetically or obtained frompeppermint or other mint oils that produces a feeling of cooling.Advantageously, (1)-menthol (natural menthol derived from peppermintoil) is used in the subject invention for analgesic effects.Alternatively, another transient receptor potential subfamily M8 (TRPM8)agonist such as icilin or eucalyptol can be used.

The formulations of the invention can include 1-20%, 5-15% by wt, or10-20% by weight menthol.

Methyl Salicylate and Camphor

The formulations can also include methyl salicylate (1-20% by wt, 5-15%by wt, or 10-20% by wt), and camphor (1-20% by wt, 2-10% by wt, or10-20% by wt). See Examples 12 and 13 below.

Phenol

Phenol cools and numbs skin on contact, making it an effective topicalanalgesic ingredient. It also kills germs, and reduces the risk forinfection in minor skin irritations. It has been used medically for over100 years, for these and other applications. Because it can improve theeffectiveness of a preparation at relieving itching, phenol is added toformulations meant for the relief of insect bites and stings, sunburn,and other painful and itchy skin conditions.

The formulations of the invention can include 0-4.6 wt. %,advantageously 0.1-0.5 wt. % phenol.

Eugenol/clove oil and thymol/thyme oil can be added in addition to, oras alternative to phenol.

Anti-Inflammatory Agents

An effective amount of an inflammation control component, which reducesor relieves inflammation, swelling, redness, and/or pain in the jointsand muscles associated with inflammation, can be added.

Anti-Inflammatory Polyphenols and Sesquiterpenes

Many polyphenols are known to have anti-inflammatory activity. Examplesare flavonoids (e.g. apigenin) and curcumin. Apigenin offers some ofnature's most potent and effective anti-inflammatory and anti-oxidantproperties. It can be included in the formulation to further enhancetherapeutic efficacy. Apigenin has a broad range of anti-inflammatoryproperties and has been cited for the ability to block the production ofcompounds that cause pain; e.g., the arthritis causing substancecyclooxygenase (COX). The addition of apigenin to a mixture of capsaicinin the constituents of the subject pain relieving formulations can beaccomplished using the high temperature surfactant technology whereapigenin is first dissolved in PS80 at elevated temperatures to form aconcentrate that is then added to the mixture (see US Application US2011/0311592 A1).

αBisabolol is another potent anti-inflammatory sesquiterpene which isknown to also have anesthetic, anti-irritant, anti-inflammatory,anti-fungal and anti-microbial properties. αBisabolol is alsodemonstrated to enhance the percutaneous absorption of certainmolecules. αBisabolol helps transport active ingredients transdermallyby enhancing skin penetration. (R. Kadir and B. W. Barry.Alpha-Bisabolol, a Possible Safe Penetration Enhancer for Dermal andTransdermal Therapeutics. Int. J Pharm. 70:87-94 (1991).)

NSAIDs/Diclofenac Sodium

In further embodiments of the invention, a Non-SteroidalAnti-Inflammatory Agent (NSAID) is co-administered with the TRPV-1selective agonist formulations. The NSAID and the TRPV-1 selectiveagonist can be administered together as a single composition (where atopical NSAID is used) or administered as separate compositions (where atopical or not topical NSAID is used). The NSAID can be administeredbefore, after or at the same time as the TRPV-1 selective agonist by thesame or different routes of administration. For example, the TRPV-1selective agonist can be administered topically while the NSAID agentcan be administered orally, topically or parentally. NSAIDs useful asadjunctive agents in the formulations of the present invention includeaspirin (acetylsalicylic acid), ibuprofen, naproxen, diclofenac,benoxaprofen, ketoprofen, indomethacin etc., and mixtures thereof. Asused herein, “NSAID” does not include methyl salicylate.

Combining an NSAID such as a diclofenac salt with capsaicin in a topicalformulation combines two established pain relieving agents whichfunction via two different mechanisms of action (MOAs); i.e., TRPV1nerve defunctionalizer and a potent COX-2 inhibitor. Solubility studieswere conducted (see below) and formulations were prepared containing theNSAID, diclofenac sodium, together with the TRPV1 selective agonist,capsaicin, utilizing the subject invention.

TABLE 3 lists components of several prepared capsaicin formulations.These formulations are discussed in the Examples.

TABLE 3 Ingredients Of Capsaicin Topical Formulations No. 1 No. 2 No. 3No. 4 No. 5 No. 5A No. 6 0.25% 0.25% 2% 2% 5% 5% 10% lngredient CapCap-HA Cap-HA Cap-HA Cap-RA Cap-HA Cap-HA Topical Ranges Form 2 Form 2Form 2 Form 3 Form 2 Form 2 Form 2 Ingredients (Wt. %) Function (Wt. %)(Wt. %) (Wt. %) (Wt. %) (Wt. %) (Wt. %) (Wt. %) ⁽¹⁾ Capsaicin 0.1-10  Defunctionalization of 0.25 0.25 2.0 2.0 5.0 5.0 10 TRPV-1 sensoryneurons Hyaluronic Acid  0-0.5 Viscosity enhancer & — 0.20 0.15 0.100.15 0.15 0.15 ~1,000K Daltons moisturizing agent Hyaluronic Acid  0-0.5Viscosity enhancer & — 0.30 0.35 0.40 0.35 0.35 0.35 ~11K Daltonsmoisturizing agent Ethyl Alcohol 1-20 Solvent 20 20 20 20 20 20 20 DGME0-10 Solvent & penetration 10 10 10 10 10 10 10 enhancer PropyleneGlycol 0-10 Solvent & penetration 10 10 10 10 10 10 10 enhancer ⁽²⁾Polysorbate 80 0-15 Surfactant, emulsifier & — — 2 2 — 10 — solubilizingagent ⁽³⁾PEG-40 0-15 Surfactant, emulsifier & — 0.50 5 5 10 — 15Hydrogenated solubilizing agent Castor Oil Water 30-60  Solvent q.s.q.s. q.s. q.s. q.s. q.s. q.s. Note: ⁽¹⁾ Trans-Capsaicin, AversionTechnologies Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, USP 30⁽²⁾ Super-refined Polysorbate-80, Croda Inc., Edison, NJ ⁽³⁾Cremophor RH20, BASF Corp, Florham Park, NJ

In other embodiments, the formulation can be a spray or gel. Topicalcompositions of the present invention can be formulated as an emulsionusing water and a surfactant or emulsifying system, along with theliquid formulations discussed above.

Methods of Making the Formulations

The method of making the formulation containing capsaicin and hyaluronicacid includes the preparation of hyaluronic acid and capsaicin solutionsfollowed by the blending of these solutions to produce the formulation.Typically, the preparation of the hyaluronic acid water solution(composed of a mixture containing 70 wt. % hyaluronic acid with amolecular weight ˜11 kDaltons, and 30 wt. % hyaluronic acid with amolecular weight of ˜1,000 kDaltons, was added to an alcohol mixturesolution containing 0.25 wt. % to 10 wt. % capsaicin dissolved insolublizing (penetrating) agents consisting of ethyl alcohol, propyleneglycol, and polyoxy 40 hydrogenated castor oil or PS80 (balance water).Adjusting the relative percentages of the hyaluronic acid molecularweights and surfactant composition resulted in variation of viscosity ofthe mixture. Example 1 provides details of the preparation of a 2 wt. %capsaicin HA formulation. Methods of making other capsaicinoidformulations are similar to the above.

Methods of Using the Formulations

Pain

The compositions of the present invention discussed above can be usedfor treating various conditions associated with pain by attenuating painat a specific site. The components of the formulations are typicallyadministered concomitantly. Examples of conditions to be treatedinclude, but are not limited to, nociceptive pain (pain transmittedacross intact neuronal pathways), neuropathic pain (pain caused bydamage to neural structures), pain from nerve injury (neuromas andneuromas in continuity), pain from neuralgia (pain originating fromdisease and/or inflammation of nerves), pain from myalgias (painoriginating from disease and/or inflammation of muscle), pain associatedwith painful trigger points, pain from tumors in soft tissues, painassociated with neurotransmitter-dysregulation syndromes (disruptions inquantity/quality of neurotransmitter molecules associated with signaltransmission in normal nerves) and pain associated with orthopedicdisorders such as conditions of the foot, knee, hip, spine, shoulders,elbow, hand, head and neck.

Neuropathic pain generally involves abnormalities in the nerve itself,such as degeneration of the axon or sheath. For example, in certainneuropathies the cells of the myelin sheath and/or Schwann cells may bedysfunctional, degenerative and may die, while the axon remainsunaffected. Alternatively, in certain neuropathies just the axon isdisturbed, and in certain neuropathies the axons and cells of the myelinsheath and/or Schwann cells are involved. Neuropathies may also bedistinguished by the process by which they occur and their location(e.g. arising in the spinal cord and extending outward or vice versa).Direct injury to the nerves as well as many systemic diseases canproduce this condition including AIDS/HIV, Herpes Zoster, syphilis,diabetes, and various autoimmune diseases. Neuropathic pain is oftendescribed as burning, or shooting type of pain, or tingling or itchingpain and may be unrelenting in its intensity and even more debilitatingthan the initial injury or the disease process that induced it.

The receptors involved in pain detection are aptly enough referred to asnociceptor-receptors for noxious stimuli. These nociceptors are freenerve endings that terminate just below the skin as to detect cutaneouspain. Nociceptors are also located in tendons and joints, for detectionof somatic pain and in body organs to detect visceral pain. Painreceptors are very numerous in the skin, hence pain detection here iswell defined and the source of pain can be easily localized. In tendons,joints, and body organs the pain receptors are fewer. The source of paintherefore is not readily localized. Apparently, the number ofnociceptors also influences the duration of the pain felt. Cutaneouspain typically is of short duration, but may be reactivated upon newimpacts, while somatic and visceral pain is of longer duration. It isimportant to note that almost all body tissue is equipped withnociceptors. As explained above, this is an important fact, as pain hasprimary warning functions. Nociceptive pain preferably includes, but isnot limited to post-operative pain, cluster headaches, dental pain,surgical pain, pain resulting from severe burns, postpartum pain,angina, genitor-urinary tract pain, pain associated with sports injuries(tendonitis, bursitis, etc.) and pain associated with joint degenerationand cystitis.

Topical preparations of the compositions of the present invention finduse as a topical therapy for a variety of skin disorders that involvepain and itching, such as postherpetic neuralgia, diabetic neuropathy,psoriasis, cluster headache, postmastectomy pain syndrome, rhinopathy,oral mucositis, cutaneous allergy, detrusor hyperreflexia, loinpain/hematuria syndrome, neck pain, amputation stump pain, reflexsympathetic dystrophy, pain due to skin tumor and arthritis, includingrheumatoid arthritis, osteoarthritis, diabetic neuropathy, psoriasis,pruritus (itching), cluster headache, post-surgical pain, tendonitis,oral pain, and pain caused by injury, amongst others. The formulationscan be used to relieve aches and pains of muscles and joints.

In addition, the preparations of the present invention also find use intopical therapy for: sciatica, fibromyalgia, gout, shingles, eczema,cutaneous allergy conditions, cutaneous inflammatory conditions,cutaneous microbial/fungal infections, trigeminal neuralgia, sinus andnasal congestion, sinus pressure, sinusitis, rhinitis, allergicrhinitis, hyperreactive rhinopathy, nasal polyps, nasal obstruction,sinus infection, dry eye syndrome, chronically dry eyes, anal/genitalitch, perianal disease, brachioradial puritus, hemorrhoids,onychomycosis, aural stimulation for non-obstructive dysphagia toimprove swallowing function, tinnitus, migraines, dandruff and hairgrowth.

As used herein, a “therapeutically effective amount” refers to thequantity or dose of an agent to produce a clinically desired result suchas a biological or chemical response, or reduction or elimination of asymptom of a disease or condition, e.g. reduction in or elimination ofpain

Administration

Topical

The compositions of the present invention can be used topically byapplying over an area to be treated. A typical method of use is to applyor rub the formulation over the entire area, until the formulationdisappears, and use about 1 to 3 or 4 times daily. Additionally, theamount of formulation used can be gradually increased with eachsuccessive application. Topical administration can continue for 1-7days, weeks, or months.

When combined with ingredients disclosed herein, the amount ofcapsaicinoid (e.g. trans-capsaicin) in the topical preparation can befrom 0.075-30 wt. %, 0.2 wt. % to 30 wt. %, between 1 wt. % and 20 wt.%, e.g. 1 wt. %, 5 wt. %, 10 wt. %, and 20 wt. %.

In certain embodiments, the administration of a TRPV1 selective agonist,such as capsaicin, formulations at the discrete site provides painattenuation or pain relief for at least about 48 hours to about 16weeks.

Several methods are available for the dispensing of the capsaicinformulations on the skin's surface. TRPV1 selective agonist containingformulation can be applied by physical means including applicator pads,swabs, or other devices intended to apply the formulations in a thinfilm such as roller bottles, felt tip or sponge tip applicators.

Roller Bottles

For liquids formulations, dispensers can include bottles with aconstriction to facilitate fluid droplet application to the skin.Especially advantageous for capsaicin containing liquid formulations aretubes and/or bottles with a sponge or a ‘roll on’ applicator.

Roll on bottles (also referred to as roller bottles) are especiallyadvantageous. The roll on bottle greatly simplifies the dispensing ofthe fluid on the skin's surface. No finger rubbing or Q-tip applicationis required. The movement of the roller ball on the skin massages thefluid into the skin.

The roll on bottle has a plastic, glass or metal roll on ball and glassor suitable plastic housing. As the ball rolls it picks up the solutionand applies it to the skin's surface. The caps of roll on bottles maycontain a special ring on the inner side. This ring presses on the ballwhen the cap is tightly shut. The pressure on the ball prevents leakageof the product.

After filling the bottles, the roll on housing and ball are fitted intothe mouth of the bottle. The roll on housing and ball is fitted bypushing the housing into the mouth of the bottle.

Precise control over where the formulation is applied important. Theroller-ball provides a more precise control where the formulation is tobe applied, to avoid contact with eyes, contact lenses, tender skin,clothing, etc. The “roll on bottle” minimizes the likelihood of causinglip and/or eye burning since finger application is not required tospread a film of the capsaicin solution on the body.

The roll on bottle configuration allows the TRPV1 selective agonistcompositions to be applied as a thin homogeneous film. Generally, theapplication of a thin film formulation is rapidly absorbed into theskin's surface following application. In several embodiments,substantially complete disappearance of the film is complete within 15minutes following application, and more usually within 10 minutes, orwith some embodiments, even less than 5 minutes after application.

Kits

The invention also includes kits comprising a liquid TRPV1 selectiveagonist composition, and a sustained release agent and surfactant, and anon-occlusive applicator device. The kit can also include a cleaningsolution for removal of residual TRPV1 selective agonist such aspolyethylene glycol.

The present invention will be further understood after carefulconsideration is given to the following non-limiting examples thereof.

EXAMPLES Example 1

Preparation of 100 Grams of “2% Cap-HA Form 2” Topical Formulation

Ingredients:

-   -   2 grams of Trans-Capsaicin Powder, Aversion Technologies, Bowie,        Md., USP 30    -   0.15 grams of Sodium Hyaluronic Acid Powder, Making Cosmetics        Inc., Snoqualmie, Wash.    -   0.35 grams of Sodium Hyaluronic Acid (SLMW) Powder, Making        Cosmetics Inc., Snoqualmie, Wash.    -   20 grams of Ethyl Alcohol, Graves Grain Alcohol, 190 Proof    -   10 grams of DGME (Ethoxydiglycol), Lotioncrafter Inc.,        Eastsound, Wash.    -   10 grams of Propylene Glycol, Lotioncrafter Inc., Eastsound,        Wash.    -   2 grams of Super-refined Polysorbate 80, Croda Inc. Florham        Park, N.J.    -   5 grams of Cremophor RH 20, BASF Corp, Florham Park, N.J.    -   q.s. Distilled Water

Step I—Preparation of the Hyaluronic Acid Solution

-   -   1. Obtain the “tare weight” of a 200 cc Pyrex beaker & add 0.15        grams of Sodium Hyaluronic Acid Powder and 0.35 grams of Sodium        Hyaluronic Acid (SLMW) Powder.    -   2. Slowly add cold (˜40° F.) 50 grams of distilled water to the        mixture from Step 1 while vigorously stirring, Set aside this        mixture for 2 hours while occasionally stirring until all the        powder is dissolved and a uniformly optically clear mixture is        achieved.

Step II—Preparation of the Capsaicin Solution

-   -   1. Add 2 grams of Trans-Capsaicin powder to a 140 cc Pyrex        beaker.    -   2. Add 20 grams of Ethyl Alcohol to the capsaicin powder in Step        1 and slowly stir.    -   3. Add 10 grams of DGME (Ethoxydiglycol) to the mixture of Step        2 and slowly stir.    -   4. Add 10 grams of Propylene Glycol to the mixture of Step 3 and        slowly stir.    -   5. Stir the solution mixture from Step 4 and heat on a hot plate        to a temperature of ˜40° C. until all the trans-capsaicin powder        is completely dissolved.    -   6. Allow the solution from Step 5 to cool to ambient        temperatures.

Step III—the Blending of Mixtures from Steps I & II to Produce the “2%Cap-HA Form 2” Formulation

-   -   1. Add the liquid contents from STEP II to the HA mixture of        STEP I and thoroughly stir.    -   2. Add 5 grams of Cremophor RH 20 to the mixture from Step 1 and        thoroughly stir.    -   3. Add 5 grams of Super-refined Polysorbate 80 to the mixture        from Step 2 and thoroughly stir.    -   4. The mixture from Step 4 is heated to about 50° C. on a hot        plate while stirring.    -   5. The mixture from Step 4 is cooled to ambient temperatures.    -   6. The mixture from Step 8 is now ready for subsequent        packaging.        Additional Method of Preparation of 100 Grams of the “2% Cap-HA”        Topical Formulations        Ingredients:    -   Trans-Capsaicin Powder, CAS #404-86-4, Formosa Labs, Taoyuan,        Taiwan    -   Sodium Hyaluronic Acid Powder (˜1,000 kDa), Making Cosmetics        Inc., Snoqualmie, Wash.    -   Sodium Hyaluronic Acid (SLMW) Powder, Making Cosmetics Inc.,        Snoqualmie, Wash.    -   Ethyl Alcohol, Graves Grain Alcohol, 190 Proof    -   DGME (Ethoxydiglycol), Lotioncrafter Inc., Eastsound, Wash.    -   Propylene Glycol, Lotioncrafter Inc., Eastsound, Wash.    -   Polysorbate 80, Croda Inc. Florham Park, N.J.    -   Cremophor RH 20, BASF Corp, Florham Park, N.J.    -   Distilled Water        Step I—Preparation of the Hyaluronic Acid Solution        1. To a “tared weight” 500 cc Pyrex beaker add 1.95 grams of        Sodium Hyaluronic Acid Powder (˜1,000 kDa) and 1.05 grams of        Sodium Hyaluronic Acid (SLMW, ˜20 kDa) Powder.        2. Slowly add 297 grams of ˜40° F. distilled water to the beaker        from Step 1 with stirring at nominally 500 rpm for nominally 5        minutes. Set this mixture aside for at least 2 hours and        occasionally stir until all the powder is dissolved and a        uniformly optically clear solution is achieved.        Step II—Preparation of the Capsaicin Solution        1. To a “tared weight” 140 cc Pyrex beaker add 2 grams of        Trans-Capsaicin powder.        2. Add 20 grams of Ethyl Alcohol to the capsaicin powder in Step        1 and slowly stir at about 50 rpm with a spatula.        3. Add 10 grams of DGME (Ethoxydiglycol) to the mixture of Step        2 and slowly stir at about 50 rpm with a spatula.        4. Add 10 grams of Propylene Glycol to the mixture of Step 3 and        slowly stir at about 50 rpm with a spatula.        5. Add 7 grams of surfactant (such as Polysorbate-80 or        Cremophor RH 20) to the mixture of Step 4 and slowly stir at        about 50 rpm with a spatula.        6. Stir the solution mixture from Step 5 at about 50 rpm with a        spatula while heating on a hot plate to a temperature of ˜50° C.        until a uniform solution is achieved.        7. Allow the solution from Step 6 to cool to ambient        temperature.        Step II—the Blending of Mixtures from Steps I & II to Produce        the “2% Cap-HA” Formulation.        1. Slowly add 51 grams of the HA mixture of STEP I to the        Capsaicin Solution of STEP II while stirring at about 50 rpm        with a spatula.        2. Stir the solution mixture from Step 1 at about 50 rpm with a        spatula while heating on a hot plate to a temperature of ˜50° C.        until a uniform solution is achieved.        3. Allow the solution from Step 6 to cool to ambient        temperature.        4. The solution from Step 3 is now ready for subsequent        packaging and use.

Example 2

Topical Application of the 0.25% Capsaicin-HA Formulations

This study assessed the tolerability of four topical capsaicinformulations by recording burning sensations and skin irritation on theright and left thigh of a 59-year old male of normal health. Theformulations were applied with a roller-ball applicator.

TABLE 4 Capsaicin Test Formulations CapZaicin ⁽¹⁾0.25% ⁽²⁾ 0.25% No-Fuss0.15% Cap Cap-HA Applicator Ingredients M/A Form-2 Form-2 (Walgreens)Capsaicin 0.15 0.25 0.25 0.15 Methyl Salicylate 50 — — — Camphor 11 — —— Liquefied Phenol 0.5 — — — Ethyl Alcohol 23.35 20 20 — (Grain alcohol)DGME — 10 10 — Propylene Glycol — 10 10 — (PG) Cremophor RH-40 — — 0.5 —Hyaluronic — — 0.15 — Acid ~1,000K Daltons Hyaluronic — — 0.35 — Acid~20K Daltons Distilled Water — 59.75 58.75 — Other 15% — — Carbomer,Menthol Glycerin, PG, SD Alcohol (35%), Tri- ethanolamine, Water Note:⁽¹⁾Formulation No. 1 in Table 3. ⁽²⁾ Formulation No. 2 in Table 3.Formulation Application

Each formulation was applied to an area measuring 25 square centimeters(5×5 cm) of skin located on the dorsal thigh. Each formulation wasrandomly assigned to either the right or left thigh. The application ofthe formulation involved a non-overlapping serpentine pass of the rollerball or applicator over the skin area that moistened the skin andresulted in a thin film of solution.

The subject evaluated tolerability prior to dosing, one minute afterdosing, at 20 minutes and 40 minutes post-dose and at 2 hours aftertaking a hot shower. Burning was quantified on a 0-10 Numeric RatingScale using the Wong-Baker faces as a guide. Skin irritation wasquantified using a standard 0 to 7 rating scale Burn Rating Scale.

The subject rated burning pain for each site of formulation application,using the following 0 to 10 numeric rating scale, with the Wong-Bakerfaces scale as a guideline.

BRIEF DESCRIPTION OF DRAWING(S)

The FIGURE shows an exemplary 0 to 10 numeric rating scale.

Skin Irritation Scale

Skin Irritation was Quantified by the Subject Using the FollowingDefinitions:

-   -   0=no evidence of irritation    -   1=minimal erythema, barely perceptible    -   2=definite erythema, readily visible; minimal edema or minimal        papular response    -   3=erythema and papules    -   4=definite edema    -   5=erythema, edema, and papules    -   6=vesicular eruption    -   7=strong reaction spreading beyond test results        Results

There was no burning or signs of skin irritation at any of the testsites of skin prior to application of the formulations.

TABLE 5 Burning & Erythema Post Application Measurements For 4 TopicalCapsaicin Formulations After Hot Shower 2 1 minute post 20 minutes post40 minutes post hours post Test application application applicationapplication Formulations Burning Erythema Burning Erythema BurningErythema Burning Erythema 0.15% M/A 2 0 2 0 0 0 3 0 ⁽¹⁾0.25% Cap 3 0 2 00 0 6 2 Form 2 very red ⁽²⁾ 0.25% Cap- 0 0 0 0 0 0 0 0 HA Form 2⁽³⁾CapZaicin 2 0 1 0 0 0 3 1 0.15% red Note: ⁽¹⁾Formulation #1 in Table3 ⁽²⁾ Formulation #2 in Table 3 ⁽³⁾Composition: Capsaicin, 0.15 wt. %;Carbomer, Glycerin, PG, SD Alcohol (35%), Triethanolamine, Water

CONCLUSIONS

The 0.15% M/A formulation demonstrated tolerability comparable to thatof CapZaicin. Burning scores were identical at 1 minute and 40 minutespost application; however at 20 minutes post application the 0.15% M/Aformulation was 1 unit higher in scored burning. Skin irritation scoreswere identical at 1 minute, 20 minutes and 40 minutes post application;however CapZaicin induced skin reddening following a hot shower 2 hourspost application whereas the 0.15% M/A formulation did not induce skinirritation.

The addition of 1% hyaluronic acid dramatically reduced the burningsensation and skin irritation induced by a 0.25% capsaicin aqueousformulation containing ethoxydiglycol and propylene glycol aspenetration enhancers.

Example 3

Topical Application of the 0.25% Capsaicin-HA Formulations

A group of 2 adult males and 2 adult females of normal health andranging in ages from 35 to 55 applied multiple topical application of 4formulations from 3.7 ml roller-ball applicators as noted in TABLE 6.The subjects noted that the 0.25 wt. % HA/capsaicin formulation was themost tolerable in term of the burning and erythema ratings. The averageburning and erythema ratings for the 4 subjects are summarized in TABLE6.

TABLE 6 Burning & Erythema Post Application Measurements For 4 TopicalCapsaicin Formulations (Average of 4 Subjects) After Hot Shower 2 1minute post 20 minutes post 40 minutes post hours post Test applicationapplication application application Formulations Burning ErythemaBurning Erythema Burning Erythema Burning Erythema 0.15% MIA 0.2 0 2.5 01.2 0.3 4.7 1 ⁽¹⁾0.25% Cap 0.8 0 1.6 0.5 1.3 0.5 4.0 2 .6 Form 2⁽²⁾0.25% Cap- 0.3 0 0.6 0.3 0.6 0.5 2.3 0.9 HA Form 2 ⁽³⁾CAPSAICIN 0.6 01.7 0.5 1.3 1.0 3.8 1.3 0.15% Note: ⁽¹⁾Formulation #1 in Table 3⁽²⁾Formulation #2 in Table 3 ⁽³⁾Composition: Capsaicin, 0.15 wt.%;Carbomer, Glycerin, PG, SD Alcohol (35%), Triethanolamine, Water

Example 4

Topical Application of the 2% Capsaicin-HA Formulations

A 40 year old female of normal health applied multiple topicalapplication of 2% trans-capsaicin formulations as noted in Table 3 onher forearm with a 3.7 ml roller-ball applicator. Burning sensationswere rated on a scale of 0-10. Erythema (reddening) was rates on a scaleof 0-10. (0 no erythema). Erythema (reddening) was rated on a scale of0-10. The subject experienced the absence of both burning and erythemafor both the 2% Cap-HA Form 2 and 2% Cap-HA Form 3 formulations. Burningand stinging recordings for the 2% M/A formulation of <3 wereexperienced for 60 minutes post application time frame. Details of thesubject's comments relating to the topical application of the 3formulations are summarized in the Tables below.

-   -   A) 2% Cap-HA Form 2 (Formulation 3 in Table 3)—Initially this        application site showed no noticeable sensitivity. No        irritation/erythema throughout the test. There was no burning        sensation or redness prior to the 60 minute timepoint. Upon        washing of the product in hot water, a slight itching sensation        and erythema occurred, at time of reading both were at a 1. This        quickly reached a zero within 30 minutes of washoff.    -   B) 2% Cap-HA Form 3 (Formulation 3 in Table 3)—Initially this        application site showed no noticeable sensitivity. No        irritation/erythema throughout the timeframe. It is important to        note there was what could be described as a pleasant warming of        the area 18 hours later when showering. This warming dissipated        within 30 minutes post shower.    -   C) ⁽¹⁾2% MA—Initially this application site showed barely        noticeable sensitivity, described as an itching sensation. There        was mild irritation/erythema upon initial application. The        burning sensation increased to a 2.5 at the 10 minute mark. The        burning sensation gradually dissipated to a mild itching. The        burning sensation increased to a 3 immediately upon exposure to        hot water and remained at this level for 10 minutes following.        Pain then gradually decreased to 0 over the course of 40 minutes        following wash off. No erythema or pain was noticeable until a        shower the next day. At which time there was a light erythema        and a mild burning characterized as a 3. This pain dissipated        within 30 minutes.

-   Note: (¹) Composition: Capsaicin. 2 wt. %: Methyl Salicylate, 50 wt.    %: Menthol, 15 wt. %: Camphor. 11 wt. %: Ethyl Alcohol. 19.5 wt. %:    Phenol 1.35 wt. %. Water, 1.15 wt.

TABLE 7 Burning & Erythema Post Application Measurements 1 minute post10 minutes post 20 minutes post 30 minutes post 45 minutes post 60minutes post Test application application application applicationapplication application Formulations Burning Erythema Burning ErythemaBurning Erythema Burning Irritation Burning Erythema Burning Erythema⁽¹⁾ 2% Cap-HA 0 0 0 0 0 0 0 0 0 0 0 0 Form 2 ⁽²⁾ 2% Cap-HA 0 0 0 0 0 0 00 0 0 0 0 Form 3 2% M/A 1.5 1.5 2.5 2 2 3 2 3 2 3 2 3 Note: ⁽¹⁾Formulation #3 in Table 3 ⁽²⁾ Formulation #4 in Table 3 ⁽³⁾ Composition:Capsaicin, 2 wt. %: Methyl Salicylate, 50 wt. %: Menthol, 15 wt. %;Camphor, 11 wt. %; Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water,1.15 wt.

TABLE 8 Burning & Erythema Post Application Measurements Immediate PostWash-Off 18 hours later Test (with hot water) during Shower FormulationsBurning Erythema Burning Erythema ⁽¹⁾ 2% Cap-HA 1 0 1 0.5 Form 2 ⁽²⁾ 2%Cap-HA 0 0 1 0 Form 3 ⁽³⁾ 2% M/A 3 3.5 3 0.5 Note: ⁽¹⁾ Formulation #3 inTable 3 ⁽²⁾ Formulation #4 in Table 3 ⁽³⁾ Composition: Capsaicin, 2 wt.%; Methyl Salicylate, 50 wt. %; ^(Menthol), 15 wt. %; Camphor, 11 wt. %;Ethyl Alcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

Example 5

Topical Application of the 2% Capsaicin-HA Formulations

A 50-year old male of normal health applied a single topical applicationof three 2 wt. % trans-capsaicin formulations via a roller ballapplicator. The burning and erythema ratings are summarized in Table 9.Both formulations containing HA had similar burning and erythema ratingsfor the 60 minute post application duration as noted in Table 9. Thesubject rated the 2 wt. % M/A formulation as slightly more burning andmore irritating than the HA formulations. All levels of burning anderythema were considered to be well within the “tolerable” level fortopical use in the subject's opinion.

TABLE 9 Burning & Erythema Post Application Measurements 1 minute post10 minutes post 20 minutes post 30 minutes post 45 minutes post 60minutes post Test application application application applicationapplication application Formulations Burning Erythema Burning ErythemaBurning Erythema Burning Irritation Burning Erythema Burning Erythema⁽¹⁾ 2% Cap-HA 1.5 0 2 0 2.5 0.5 2.5 0.5 2.5 0.5 2.0 1 Form 2 ⁽²⁾ 2%Cap-HA 1.5 0 2 0 2.5 0.5 2.5 0.5 2.5 0.5 2.0 1 Form 3 2% M/A 1 0 2.5 0.53 1 3.5 1 3.0 0.5 2.5 1 Note: ⁽¹⁾ Formulation #3 in Table 3 ⁽²⁾Formulation #4 in Table 3 ⁽³⁾ Composition: Capsaicin, 2 wt. %; MethylSalicylate, 50 wt. %; Menthol, 1.5 wt. %; Camphor, 11 wt. %; EthylAlcohol, 19.5 wt. %; Phenol 1.35 wt. %, Water, 1.15 wt.

Example 6

Topical Application of the 5% and 10% Capsaicin Formulations

A 79 year old male took part in an evaluation of both the 5 wt. % and 10wt. % capsaicin-HA to evaluate the burning and erythema effect ofcapsaicin. The burning effect was rated on a scale of (0-10) and at thesame time erythema reddening was also determined by eye on a scale of(1-5).

Application of the 5 wt. % capsaicin-HA formulation via 3.7 mlroller-ball bottle was undertaken to achieve an initial dosing on a 25cm² (5 cm×5 cm) area of skin on his left arm, 20 cm below the elbowjoint on the underside of his left arm. Several passes of theroller-ball were undertaken to the entire 25 cm application area.

Similarly, application of 10 wt. % capsaicin-HA formulation via 3.7 mlroller-ball bottle was undertaken to achieve an initial dosing on a 25cm² (5 cm×5 cm) area of skin on his left arm, 20 cm above the elbowjoint on the upper side of the right arm. Several passes of theroller-ball were applied to the 25 cm² application area.

The observed burning and erythema results are summarized in Tables 10and 11. The subject noted a gradual increase in the burning sensation toa 3 level for the 5 wt. % capsaicin and a level 2.5 for the 10 wt. %capsaicin formulation at the 20 minute mark followed by a gradualdecrease to zero after 60 minutes. The subject noted a slight itchingthat lasted for about 5 to 15 minutes after fluid application.

In both cases the level of burning for both the 5 wt. % and 10 wt. %Capsaicin/HA formulation were well tolerated.

TABLE 10 Burning & Erythema Post Application Measurements 1 minute post10 minutes post 20 minutes post 30 minutes post 45 minutes post 60minutes post Test application application application applicationapplication application Formulations Burning Erythema Burning ErythemaBurning Erythema Burning Irritation Burning Erythema Burning Erythema⁽¹⁾ 5% Cap-HA 0 0 ⁽³⁾ 2 0 3.0 0 1.5 0 0.5 0.5 0 0 Form 2 ⁽²⁾ 10% Cap-HA0 0 ⁽³⁾ 2.50 0 2.5 0.5 2.0 0 1 0 0 0 Form 3 Note: ⁽¹⁾ Formulation #5 inTable 3 ⁽²⁾ Formulation #6 in Table 3 ⁽³⁾ Slight itching experienced

TABLE 11 Burning & Erythema Post Application Measurements Immediate PostWash-Off 18 hours later Test (with hot water) during Shower FormulationsBurning Erythema Burning Erythema ⁽¹⁾ 5% Cap-HA 1 0.5 1 0.5 Form 2 ⁽²⁾10% Cap-HA 2 0.5 0 0 Form 3 Note: ⁽¹⁾ Formulation #5 in Table 3 ⁽²⁾Formulation #6 in Table 3

Example 7

Topical Application of the 5% and 10% Capsaicin-HA Formulations

A 71-year old female of normal health applied a single topicalapplication of the 5 wt. % capsaicin-HA formulation to her left forearmand the 10 wt. % capsaicin-HA formulation to her right forearm in amanner similar to that described in Example 6. The observed burning anderythema results are summarized in TABLES 12 and 13. The level ofburning for both the 5 wt. % and 10 wt. % Capsaicin/HA formulation werewell tolerated.

TABLE 12 Burning & Erythema Post Application Measurements 1 minute post10 minutes post 20 minutes post 30 minutes post 45 minutes post 60minutes post Test application application application applicationapplication application Formulations Burning Erythema Burning ErythemaBurning Erythema Burning Irritation Burning Erythema Burning Erythema⁽¹⁾ 5% Cap-HA 0 0 ⁽³⁾ 1 0.5 3.0 0.5 2.0 0.5 0.5 0 0 0 Form 2 ⁽²⁾ 10%Cap-HA 0 0 ⁽³⁾ 3.0 1 2.5 1 2.0 0 1 0 0.5 0 Form 3 Note: ⁽¹⁾ Similar toFormulation #5 in Table 3 ⁽²⁾ Similar to Formulation #6 in Table 3 ⁽³⁾Slight itching experienced

TABLE 13 Burning & Erythema Post Application Measurements Immediate PostWash-Off 18 hours later Test (with hot water) during Shower FormulationsBurning Erythema Burning Erythema ⁽¹⁾ 5% Cap-HA 3 1 2 1 Form 2 ⁽²⁾ 10%Cap-HA 2 1 2 0 Form 3 Note: ⁽¹⁾ Similar to Formulation #5 in Table 3 ⁽²⁾Similar to Formulation #6 in Table 3

Example 8

Topical Application of 2%. 5% and 10% CAPSAICIN-HA Formulation with PS80to Rats

A small rat study was conducted utilizing the capsaicin-HA formulationsbelow:

2%, 5%, and 10% CAPSAICIN-HA FORMULATIONS (Optically Clear Single PhaseFormulations) 2 wt. % 5 wt. % 10 wt. % INGREDIENTS HA-Cap HA-Cap HA-CapCAPSAICIN (Formosa) 2 5 10 POLYSORBATE 80 7 10 13 (Super Refined -Croda) ETHYL ALCOHOL 20 20 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 10 10METHYL ETHER (DGME) PROPYLENE GLYCOL 10 10 10 ⁽¹⁾HA (~1,000K Daltons)0.17 0.17 0.12 ⁽¹⁾HA SLMW (~20K Daltons) 0.33 0.33 0.25 ⁽¹⁾DISTILLEDWATER 50.50 44.50 36.63 TOTAL 100 100 100

A single administration of the 2% and 5% capsaicin formulations for 30minutes was tolerated in the rats. A single administration of the 10%capsaicin formulation for 30 minutes was not well tolerated in the rats.

Example 9

Topical Application of 10% CAPSAICIN-HA Formulation with PS80 to a Human

A 53-year old male of normal health applied a single topical applicationof 10% trans-capsaicin hyaluronic acid (HA) PS80 solution for 120minutes prior to washing off. This formulation was formulated with PS80as the surfactant. Composition of the formulation is shown in thefollowing table.

Composition of the 10% HA-CAPSAICIN FORMULATION INGREDIENTS wt. %CAPSAICIN (Formosa) 10 POLYSORBATE 80 (PS80) 13 (Super Refined - Croda)ETHYL ALCOHOL 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 METHYL ETHER (DGME)PROPYLENE GLYCOL 10 HA (~1,000K Daltons) 0.12 HA SLMW (~20K Daltons)0.25 DISTILLED WATER 36.63 TOTAL 100

Application of formulation via 10 mg roller-ball bottle was undertakento achieve a liberal “glistening” dose over a 15 in (5 inch×3 inch) areaof skin on right knee covering half the knee cap and the space justabove the knee cap. Several passes of the roller-ball were undertaken tothe entire application area to achieve this liberal dosing offormulation.

Rating of stinging/burning (S&B) and Redness (Erythema) are shown in thetable below as a function of time following topical application.

S&B Erythema Minutes Scale 0-10 Scale 0-5 2 1 0 5 1.5 .5 10 2 1 20 2 1.530 2 1.5 40 2.5 1.5 60 2 2 80 1 1.5 90 1 1 100 0.5 0.5 120 0.5 0.5

In the table above, the S&B Scale of 0 to 10 is a representation of“stinging and burning” where a zero represents an absence of any S&B, a1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is theworst pain imaginable. Likewise, the 0 to 5 Erythema scale representsthe amount of reddening visually observed where a zero is an absence ofreddening, a 1 indicates slight reddening of the skin, a 3 indicates adark red color and a 5 is purple.

Overall subject observed a gradual onset of a slight, but verytolerable, burning and stinging sensation over the first 40 minutesfollowing application, followed by a gradual decrease after that pointuntil the 120 minute mark, at which time a very slight S&B sensationstill remained. In more detail, a slight S&B sensation rated at a 1 wasfelt after only 2 minutes, and rose to a 2 rating after 10 minutes.Maximum S&B rated at a 2.5 (on a scale of 0-10) was observed after 40minutes. The S&B sensation slowly and gradually increased prior to the40 minute mark. This maximum of 2.5 rated S&B sensation was observed tobe quite tolerable at its peak, and then and gradually dissipated beyondthe 40-minute mark. From the 40-minute mark on the subject observed agradual reduction of S&B sensation until the 100 minute mark, at whichtime the S&B level was observed as a very slight 0.5 rating (on a scaleof 1-10). This very slight 0.5 S&B rating continued until the end of the120 minute period recorded. All levels of irritation were considered tobe well within a “tolerable” level for topical use in subject's opinion.

In addition, reddening (erythema) and reduction of reddening of theentire 50 cm² application area was observed over the initial 120 minuteperiod following application. Subject observed a reddening rated at a0.5 (on a scale of 1-5) after 5 minutes, to a rating of 1.0 after 10minutes, and a rating of 1.5 after 20 minutes. This reddening rating of1.5 was the maximum level observed and lasted from the 20 minute markuntil the 40 minute mark. Reddening gradually lessened after the40-minute mark and was down to an S&B rating of 0.5 after 100 minutes.This slight reddening of 0.5 rating was still observed at the end of the120 minute period recorded. Reddening was uniform and no blotching orother form of inconsistent effect was observed. The area of reddeningdid not expand beyond the area of application: only skin area directlytreated with the formulation had erythema associated with it. Skin didnot become more sensitive during the 120 minute application of theformulation.

Example 10

Topical Application of 10% CAPSAICIN-HA Formulation with PS80 to a Human

A 41-year old female of normal health applied a single topicalapplication of 10% trans-capsaicin hyaluronic acid (HA) PS80 solutionfor 120 minutes prior to washing off. The composition of thisformulation is shown in the following table.

Composition of the 10% HA-CAPSAICIN FORMULATION INGREDIENTS wt. %CAPSAICIN (Formosa) 10 POLYSORBATE 80 (PS80) 13 (Super Refined - Croda)ETHYL ALCOHOL 20 (Grain Alcohol) ETHOXYDIGLYCOL 10 METHYL ETHER (DGME)PROPYLENE GLYCOL 10 HA (~1,000K Daltons) 0.12 HA SLMW (~20K Daltons)0.25 DISTILLED WATER 36.63 TOTAL 100

Application of formulation via 10 mg roller-ball bottle was undertakento achieve a liberal “glistening” initial dosing on a 8 in² (4 inch×2inch) area of skin on the inner right forearm. Several passes of theroller-ball were undertaken to the entire application area to achievethis liberal dosing of formulation.

Rating of stinging/burning (S&B) and Redness (Erythema) are shown in thetable below as a function of time following topical application.

S&B Erythema Minutes Scale 0-10 Scale 0-5 2 0 0 5 1 1 10 1 1 20 1 1.5 301 1.5 40 1 1.5 60 1 1.5 80 1 1.5 90 1 1.5 100 0.5 0.5 120 0.5 0.5

In the table above, the S&B Scale of 0 to 10 is a representation of“burning and stinging” where a zero represents an absence of any S&B, a1 is a slight S&B, a 5 is an intolerable amount of S&B and a 10 is theworst pain imaginable. Likewise, the 0 to 5 Erythema scale representsthe amount of reddening visually observed where a zero is an absence ofreddening, a 1 indicates slight reddening of the skin, a 3 indicates adark red color and a 5 is purple.

A slight stinging sensation rated at a 1 was felt after 5 minutes, andstayed steady until the 100 minute mark where it gradually decreased.The maximum S&B rated at a 1 (on a scale of 0-10) was observed through90 minutes. This 1 rated S&B was observed to be quite tolerable. Fromthe 100-minute mark on, the subject observed a gradual reduction of S&Bsensation. The very slight 0.5 S&B continued until the end of the 120minute period recorded. All levels of irritation were well within a“tolerable” level for topical use in subject's opinion.

In addition, reddening (erythema) and reduction of reddening of theentire application area was observed over the initial 120 minute periodfollowing application. Subject observed a reddening rated at a 1 (on ascale of 1-5) after 5 minutes, to a rating of 1.5 after 10 minutes thatcontinued past the 90 minute mark. Reddening gradually lessened afterthe 100-minute mark and was down to a 0.5 for the duration. This slightreddening of 0.5 rating was still observed at the end of the 120 minuteperiod recorded. Reddening was uniform and no blotching or other form ofinconsistent effect was observed. The area of reddening did not expandbeyond the area of application: only skin area directly treated with theformulation had erythema associated with it.

Skin did not become more sensitive during the 120 minute application ofthe formulation.

Example 11

Four Daily Dose Treatments of Osteoarthritis with a 10% Capsaicin-HAFormulation

A 59 year old man suffering from severe and advanced osteoarthritis useda 10% capsaicin hyaluronic acid formulation once a day on foursuccessive days for mitigation of osteoarthritis pain. The formulationused contained 10% w/w capsaicin along with hyaluronic acid (HA) andutilized Cremaphore RH40 as a stabilization agent (see Table below).This man was Caucasian, obese with degenerative joint disease(osteoarthritis) especially in the knees, bilaterally, with severedegeneration of medial and lateral meniscus and articular cartilagebilaterally, right greater than left. At the time, pain was marginallycontrolled with Tramadol 50-100 mg tid, giving partial relief, bringingthe pain level down to approximately 4 on the pain scale, with sharpshooting pains that scale up to 8-9.

Efficacy

The subject noted that “After treating my worse knee (right) with the10% formulation for one hour a day for four days, my pain reliefimproved to a pain level of 2, making my more troublesome knee thebetter, most pain free knee. The sharp shooting pains also improved andwere much less frequent with the momentary severe pain levels onlyreaching 5. This change for the better lasts for weeks.”

Tolerability

The subject noted that “My stinging/burning sensation while applying thetreatment was only a trace, less than 1 by my estimate. The sting/burnonly slightly increases in the shower, at most to a 1 on the pain scale.While in the shower there was a mild, manageable cough as I rinsed thetreated area, fortunately this was only momentary because theformulation washes away easily, quickly and completely.”

Overall Assessment

The subject was very pleased with the results.

Formulation Composition Table INGREDIENTS wt. % CAPSAICIN (Formosa) 10CREMOPHOR RH 40 12 ETHYL ALCOHOL (Grain Alcohol) 20 ETHOXYDIGLYCOL(DGME) 10 PROPYLENE GLYCOL 10 ⁽¹⁾ HYALURONIC ACID AQUEOUS SOLUTION 38TOTAL 100 Note: ⁽¹⁾ The Hyaluronic Acid Aqueous Solution contains 0.65wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid1,000K Daltons) and 99 wt. % Distilled Water.

Example 12

Single Dose Pulse Treatment of Osteoarthritis with a 10% Capsaicin-HAFormulation

A 79 year old man with a history of moderate to severe Osteoarthritis inmultiple joints (successful hip replacement in 2008) used a 10%capsaicin HA formulation several times for mitigation of arthritis painin both his hip and shoulder joints. The formulation used contained 10%w/w capsaicin along with hyaluronic acid (HA) and utilized CremaphoreRH40 as a stabilization agent (see Table below).

Efficacy:

The subject applied the above mentioned formulation several times onboth his left hip and his right shoulder to control osteoarthritis pain.He applied the 10% Capsaicin HA formulation on an “as needed” basis,which on average was estimated to be once every two weeks. When heapplied the formulation, he generally left it on for at least one hourprior to washing off. He did not repeat doses on back to back days, butinstead applied a single dose, and then waited until the pain returnedto apply another dose. When a single dose of this 10% capsaicinformulation with hyaluronic acid was applied, the arthritis pain wascompletely eliminated in his shoulder joint for approximately two weeks.Similarly, pain was reduced by approximately 80% when applied on hisarthritic hip joint, and significant pain did not return to his hipjoint for duration of about 2 weeks from a single dose. The average timeto return of pain in both joints was approximately 2 weeks. He was verypleased with the convenience of 1 to 2 weeks of pain relief from thecapsaicin following each single dose.

Tolerability:

The subject noted that the application of this formulation was verytolerable (not irritating). He observed no burning and stinging (B&S)irritation upon application to his shoulder joint for all applicationsto his shoulder. When he applied the formulation to his hip joint(avoiding the groin and buttocks areas) the maximum S&B sensation wasnever greater than a 2 rating on a scale of 0 to 10 (defined as zeromeaning no S&B sensation, 5 denoting intolerable pain and 10representing the worst pain imaginable). Erythema (reddening) wasnon-existent on his shoulder joint upon application, and was estimatedat a rating or 1.5 (on a scale of 0 to 5) when the formulation wasapplied to his hip joint (ratings defined as zero representing anabsence of reddening, a 3 as dark red and a 5 as purple). In terms ofboth S&B sensation and erythema, the subject found the formulation to bevery tolerable.

Formulation Composition Table INGREDIENTS wt. % CAPSAICIN (Formosa) 10CREMOPHOR RH 40 12 ETHYL ALCOHOL (Grain Alcohol) 20 ETHOXYDIGLYCOL(DGME) 10 PROPYLENE GLYCOL 10 ⁽¹⁾ HYALURONIC ACID AQUEOUS SOLUTION 38TOTAL 100 Note: ⁽¹⁾ The Hyaluronic Acid Aqueous Solution contains 0.65wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid1,000K Daltons) and 99 wt. % Distilled Water.

Example 13

Capsaicin—HA formulations containing Analgesics

A 1 wt. % hyaluronic acid water solution composed of a mixturecontaining 70% Hyaluronic Acid with a molecular weight 20K Daltons and30% hyaluronic acid with a molecular weight 1,00K Daltons, was added toan alcohol mixture solutions containing 0.25 wt. % and 2.0 wt. %Capsaicin dissolved in 20% ethyl alcohol and 10% propylene glycol and 15wt. % and 17 wt. % Cremophor™ RH 40, respectively. Optically crystalclear and moderately viscous solutions were formed. Adjusting therelative percentages of hyaluronic acid molecular weights could vary theviscosity of the mixture.

Both the 0.25% wt. % and 2.0 wt. % capsaicin formulations (see Tablebelow) as described in the foregoing paragraphs were applied to an 80year old male subject's right forearm via a 5 ml roller-ball vial. Theapplied liquid film dried in a few minutes. Minimal discomfort fromburning & stinging was experienced. Significantly, the formulationscontaining 10 wt. % methyl salicylate were relatively odor free.

CAPSAICIN-ANALGESIC-HA-FORMULATIONS ¼% 2% Cap-HA Cap-HA INGREDIENTSFUNCTION (wt. %) (wt. %) Capsaicin (Formosa) TRPV1 Agonist 0.25 2 MethylSalicylate Analgesic Agent & 10 10 Penetrant Menthol Cooling Agent & 5 5Penetrant Camphor Anesthetic Agent 2 2 Penetrant Cremophor RH 40Surfactant & 15 17 Solubilizer Ethyl Alcohol Solubilizer & 20 20 (GrainAlcohol) Penetrant Diethylene Glycol Solubilizer & 0 0 Monoethyl Ether(DGME) Penetrant Propylene Glycol Solubilizer & 10 10 Penetrant ⁽¹⁾Hyaluronic Acid Moisturizer & 37.75 34 Aqueous Solution Humectant TOTAL100 100 Note: ⁽¹⁾ The Hyaluronic Acid Aqueous Solution contains 0.65 wt.% Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid 1,000KDaltons) and 99 wt. % Distilled Water.

Example 14

Comparison of Tolerability and Erythema Following Topical Application ofTwo (2%) Capsaicin HA Formulations: Effect of the Inclusion ofAnalgesics

The purpose of this study was to evaluate tolerability and erythemacreated by the inclusion of topical analgesics to a capsaicin hyaluronicacid (HA) formulation following topical application. A 53 year old maleapplied two distinct formulations of 2% capsaicin HA (one formulationwith topical analgesics and one without) on a single knee side by side.Burning and stinging (S&B) along with skin redness were quantifiedfollowing topical application in older to evaluate the tolerability anderythema characteristics singularly and comparatively with the twoformulations. The compositions of the two formulations are shown belowas Formulation 1 (Capsaicin HA) and Formulation 2 (Capsaicin HA plusAnalgesics).

Formulation 1 Composition Capsaicin HA Formulation INGREDIENTS wt. %CAPSAICIN (Formosa) 2 CREMOPHOR RH 40 7 ETHYL ALCOHOL (Grain Alcohol) 20Diethylene Glycol Monoethyl Ether (DGME) 10 PROPYLENE GLYCOL 10 ⁽¹⁾HYALURONIC ACID AQUEOUS SOLUTION 51 TOTAL 100

Formulation 2 Composition Capsaicin HA plus Analgesics FormulationINGREDIENTS FUNCTION wt. % Capsaicin (Formosa) TRPV1 Agonist 2 MethylSalicylate Analgesic & Solvent 10 Menthol Analgesic & Cooling 5 CamphorAnalgesic 2 Cremophor RH 40 Surfactant 17 Ethyl Alcohol (Grain Alcohol)Solvent 20 Diethylene Glycol Monoethyl Ether Solvent 0 (DGME) PropyleneGlycol Solvent & Humectant 10 ⁽¹⁾ Hyaluronic Acid Aqueous Moisturizer &Humectant 34 Solution TOTAL 100

-   -   Note:    -   ⁽¹⁾ The Hyaluronic Acid Aqueous Solution contains 0.65 wt. %    -   Hyaluronic Acid SLMW (˜20K Daltons), 035 wt. % Hyaluronic    -   Acid 1,000K Daltons) and 99 wt. % Distilled Water.

Formulation 1 below is a 2% capsaicin HA formulation. Formulation 2below consists of 2% Capsaicin HA alone with several well-known naturalanalgesic compounds. Tolerability (S&B) was assessed using a scale of 0to 10, where a zero represents an absence of any S&B, a 1 is a slightS&B, a 5 is an intolerable amount of S&B and a 10 is the worst painimaginable. Likewise, the 0 to 5 Erythema scale represents the amount ofreddening visually observed on the skin where a zero rating is anabsence of reddening, a 1 rating indicates slight reddening of the skin,a 3 rating indicates a dark red color, and a 5 is purple.

A 53 year old male applied both formulations at the same time. The twoformulations were applied side by side and then Tolerability (S&B) andErythema (reddening) ratings were taken for each formulation applicationover a 120 minute period. The ratings are shown in S&B Table and RednessTable below. The tolerability of Formulation 2 (2% Capsaicin HA plusAnalgesics) was not only at the extreme low end of the tolerabilityscales by both measures, but was even lower than Formulation 1 (2%Capsaicin HA) by direct comparison. For Formulation 1, a maximum S&Brating of 2.0 and a maximum Erythema rating of 1.5 were observed by the20 minute time point. Both ratings gradually decreased to zero by the 90minute time point. For Formulation 2, a maximum S&B rating of 1.5 wasobserved at the 30 minute time point, and then gradually decreased tozero by the 90 minute time point. Formulation 2 Erythema maximum wasobserved by the 20 minute time point at a rating of 0.5 and this ratingdecreased to zero by the 60 minute time point.

S&B Table Tolerability Comparisons (Scale 0 to 10) Elapsed Time ofFormulation Formulation Rating #1 Rating #2 Rating  2 Minutes 0.5 0  5Minutes 1.0 0.5 10 Minutes 1.5 1.0 20 Minutes 2.0 1.5 30 Minutes 2.0 1.045 Minutes 1.0 0.5 60 Minutes 0.5 0 90 Minutes 0 0 120 Minutes  0 0

Redness Table Erythema Comparisons (Scale 0 to 5) Elapsed Time ofFormulation Formulation Rating #1 Rating #2 Rating  2 Minutes 0 0  5Minutes 0.5 0 10 Minutes 1.0 0 20 Minutes 1.0 0.5 30 Minutes 1.5 0.5 45Minutes 1.0 0.5 60 Minutes 0.5 0 90 Minutes 0 0 120 Minutes  0 0

Despite containing 2% capsaicin, both formulations were observed to bevery tolerable in terms of both the stinging and burning sensation(S&B), as well as visual reddening (Erythema). Furthermore, addition ofanalgesics to 2% Capsaicin HA (Formulation 2, Capsaicin HA plusAnalgesics) resulted in lower ratings of both S&B sensation and erythemarelative to 2% Capsaicin HA (Formulation 1, Capsaicin HA).

Example 15

Single Dose Treatment of Back Muscles with a 10% Capsaicin-HAFormulation

A 79 year old man used a 10% capsaicin HA formulation for mitigation ofpain in his back due to his back muscles seizing up in spasm and causingintense pain. The formulation used contained 10% w/w capsaicin alongwith hyaluronic acid (HA) and utilized Cremaphore RH40 as astabilization agent (see Table below).

Efficacy:

A 79 year old man still with an active lifestyle (and a history of backproblems) was playing tennis when his back “went out” while picking up atennis ball. He collapsed on the court, and any attempt to move causedhim intense pain that he rated as an 8 on a scale of 0 to 10 (where zerois an absence of pain and a 10 is the worst pain imaginable). Thesubject was practically immobilized and lay flat on his back on thetennis court and required assistance to get up and be moved to a bed. Hereported that the muscles in his middle and lower back has seized upfrom an abnormality with a nerve in his back (doctors had previouslyexplained to him). Previously when this problem had occurred he requiredmany days of bed rest to recover. Once in bed, he requested his wife toapply 10% capsaicin and hyaluronic acid (with Cremaphore RH40)formulation over a 12″×12″ area on his back where the muscles had seizedup in spasm. About 90% of the treatment area consisted of muscle withthe spine in the middle. When a single dose of this 10% capsaicinformulation with hyaluronic acid was applied, the pain was eliminated inhis back within 20 minutes following application. The muscles in hisback had relaxed. The muscle spasms were gone and he began to movearound in normal motions without pain over the course of one hour. Atthe end of two hours, he felt normal and went out and resumed his tennisgame. The capsaicin with HA formulation had provided relief thatpreviously had only been achieved from days of bed rest and restrictedactivity.

Tolerability:

The subject observed the topical application of this formulation to bevery tolerable (not irritating). He observed only minor Stinging andBurning (S&B) irritation upon application to his back. When theformulation was applied to the relatively large area on his back hegradually felt a warming sensation grow over the initial 2 to 3 minutesfollowing application. The subject noted this was a comfortingsensation. He observed that at its maximum, the Stinging and Burningsensation (S&B) was rated at no more than a 2.5 on a scale of 0 to 10(defined as zero meaning no S&B sensation, 5 denoting intolerable painand 10 representing the worst pain imaginable). Erythema (reddening) waspresent across the entire area of application very evenly, and appearedat its worst to look like a mild sunburn. At its worst, this erythemawas estimated at a rating of 1.5 on a scale of 0 to 5: where a zerorepresents a complete absence of erythema, a 1 is slight reddening, a 3as dark red and a 5 as purple. In terms of both S&B sensation anderythema, the subject found the formulation to be very tolerable.

Formulation Composition Table INGREDIENTS wt. % CAPSAICIN (Formosa) 10CREMOPHOR RH 40 12 ETHYL ALCOHOL (Grain Alcohol) 20 ETHOXYDIGLYCOL(DGME) 10 PROPYLENE GLYCOL 10 ⁽¹⁾ HYALURONIC ACID AQUEOUS SOLUTION 38TOTAL 100 Note: ⁽¹⁾ The Hyaluronic Acid Aqueous Solution contains 0.65wt. % Hyaluronic Acid SLMW (~20K Daltons), 0.35 wt. % Hyaluronic Acid1,000K Daltons) and 99 wt. % Distilled Water.

Example 16

Tolerability of a 5% Capsaicin-HA Formulation Containing Polysorbate 80to Knees Afflicted with Osteoarthritis

Formulation Composition Table Ingredients Function Wt. % CapsaicinDefunctionalization of 5.0 TRPV-1 sensory neurons Hyaluronic Viscosityenhancer & 0.15 Acid ~1,000K moisturizing agent Daltons HyaluronicViscosity enhancer & 0.35 Acid ~11K moisturizing agent Daltons EthylAlcohol Solvent 20 DGME Solvent & penetration 10 enhancer PropyleneGlycol Solvent & penetration 10 enhancer Polysorbate 80 Surfactant,emulsifier & 10 solubilizing agent Water Solvent q.s.

A 70 year old man applied a 5% capsaicin HA formulation containingpolysorbate 80 (composition shown in table above) to both of his kneesafflicted with osteoarthritis. The man experienced no burning andstinging or pruritus for 32 minutes (duration of study) followingtopical application.

While the invention has been described with reference to exemplaryembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims.

All documents and other information sources cited herein are herebyincorporated in their entirety by reference.

The invention claimed is:
 1. A composition comprising: i) 0.075-20% byweight of a capsaicinoid, ii) an extended release agent to slow therelease of said capsaicinoid from said composition upon administrationof said composition to a mammal, and iii) a surfactant, wherein saidcomposition reduces or eliminates the burning and stinging created bysaid capsaicinoid upon topical administration.